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BCAA VALINE CAN CAUSE DIABETES AND MAKE YOU FAT!

Brian Turner

Posted on December 04 2019

New Research:

 

By Steve Blechman

 

Research studies have found that branched-chain amino acids (BCAAs) are associated with diabetes and obesity, and the branched-chain amino acid valine is the culprit! A study published in the journal Metabolife (January 14, 2019) found a strong association between branched-chain amino acids and the risk of incident for type 2 diabetes in China. The branched-chain amino acid valine had the highest risk prediction of incidents of type 2 diabetes! These findings could aid in diabetes risk assessment in the Chinese and global population!

There’s an overwhelming amount of evidence over the years that elevated branched-chain amino acids are associated with obesity and insulin resistance. A meta-analysis study (Acta Diabetologica, November 9, 2018) found that oral BCAA elevates circulating dietary BCAA and were positively and inversely related to type 2 diabetes mellitus and overweight/obesity risk respectively! The researchers said, “Eight articles on randomized clinical trials of oral BCAA supplementation and seven articles on dietary BCAA intake and type 2 diabetes/obesity risks were eligible for inclusion in our meta-analysis.”

Branched-chain amino acids supplements (BCAAs) have been associated with insulin resistance in obese individuals. Recently, the valine catabolite 3-hydroxyisobuterate (3HIB) was shown to promote insulin resistance in skeletal muscle by increasing lipid content in vivo. The purpose of this study was to investigate the mechanistic effects of 3HIB on skeletal muscle insulin signaling, metabolism, and related gene expression in vitro. These findings were recently published in the Journal of Nutrition Research (June 2019). This most recent study found that 3HIB can reduce muscle insulin sensitivity and support a role of 3HIB in the development of insulin resistance. This study is significant because it confirms the mechanism of 3HIB and insulin resistance in muscle!

As I mentioned above, high levels of BCAAs are associated with hyperglycemia, diabetes and insulin resistance. In a most recent study in the journal Mediators of Inflammation, on November 11, 2019, researchers undertook a study, “aimed at assessing circulating valine concentrations in subjects with type 2 diabetes,” noting that “Circulating valine level might be a novel biomarker for type 2 diabetes.”  

The researchers analyzed blood valine levels in type 2 diabetes after sitagliptin treatment, an anti-diabetic drug. “Valine levels were higher in type 2 diabetes patients, while decreased in sitagliptin monotherapy.” Research has also shown that the anti-diabetic drug metformin can also lower valine in the blood of diabetics. “These results suggest that valine might be involved in the pathogenesis in type 2 diabetes,” the researchers said.

It was reported in the journal Nature Medicine in 2015 that valine catabolite 3-hydroxyisobuterate (3HIB) 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 3HIB prevented the uptake of fat. Other studies support the negative effect of 3HIB on insulin signaling with elevated 3HIB 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-hydroxyisobuterate (3HIB), 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 3HIB acted as a shuttle in muscle cells, allowing blood vessels in skeletal muscle tissue to move fat into skeletal muscle. The more 3HIB, the more fat was transported — and conversely, when scientists blocked 3HIB from being made, there was less uptake of fat into skeletal muscle.”

In another most recent study published in the American Journal of Physiology-Endocrinology and Metabolism on November 26, 2019, it was found that leucine can prevent intracellular muscle lipid accumulation and storage in skeletal muscle, which is commonly observed in obese patients, resulting in mitochondrial damage. We normally store fat in adipose sites (often referred to as white fat) mainly around our waistline and hips, but we also store fat in muscles. Fatty muscles interfere with the function of insulin a hormone produced in the pancreas and can cause insulin resistance, elevated blood sugar and type 2 diabetes. 

An article published in the The New York Times on December 3, 2019 reported that, “cyclists who peddled on an empty stomach burned twice as much fat.” This new study that was reported in the Times’ article was recently published in the Journal of Clinical Endocrinology and Metabolism. The study found that exercising on an empty stomach can lower muscle fat! 

The latest research supports my position over the last two years that BCAAs are linked to insulin resistance, diabetes, obesity, with valine being the culprit! That’s why I have always recommended leucine as a dietary supplement rather than BCAA mixtures containing valine.

Researchers found that leucine supplementation can increase insulin sensitivity by activating SIRT1 activity and promote mitochondrial biogenesis and prevent the mitochondrial dysfunction in skeletal muscle. By increasing insulin sensitivity, leucine may enhance fat loss and improve lean body mass. Research has shown that leucine amplifies the effect of the diabetic drug metformin on insulin sensitivity and glycemic control in diet-induced obesity. Adding leucine to metformin has been shown to be synergistic, enabling a 65% to 80% metformin reduction with no loss of diabetic efficacy and a 40% metformin dose reduction in a recent clinical trial (Diabetes, June 12, 2016; Metabolism 2016 and Alimentary Pharmacology & Therapeutics, 2018). Metformin has been approved by the FDA for over 25 years as an anti-diabetic drug and has recently been reviewed as a possible FDA-approved anti-aging drug. Recent research has also shown that metformin can lower elevated valine levels in diabetics.

A meta-analysis that combined the results of seven studies showed that BCAAs or leucine supplements are best taken after exercise, not before or during exercise (intra-workout) for reducing muscle soreness and creatine kinase, a marker of muscle damage, better than rest alone. Leucine consumption before your workout promotes sluggishness and fatigue. Recent research has shown that leucine competitively inhibits the dopamine precursor tyrosine into the brain and reduces dopamine levels. Increased dopamine allows the body to perform at higher levels than normal. Increasing dopamine reduces fatigue and increases mental arousal, focus, confidence, and greater levels of motivation. Pre-workout leucine and BCAA consumption is not best for optimal muscle performance

Leucine is the key anabolic trigger to protein synthesis! For best results as an anabolic trigger, take 5 grams of leucine, as found in Advanced Molecular Labs™ (AML™) Post Workout, on an empty stomach after resistance training workout and 15-30 minutes before a post-workout meal. 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. 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.

 

References:

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  1. Skip Breakfast Before the Gym by Gretchen Reynolds. NY Times. December 3, 2019 
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  1. 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. sciencedaily.com/releases/2018/05/180517113847.htm
  1. 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
  1. NutraIngredients-USA.com, December 17, 2017. Nathan Gray. Could dropping specific amino acids from diet be key to weight loss? 
  1. 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 
  1. 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. 
  1. 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.
  1. 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 
  1. 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.
  1. 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.
  1. Yoon M-S. The emerging role of branched-chain amino acids in insulin resistance and metabolism. Forum Nutr.2016; 8: 405-17.
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  1. 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
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  1. 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.
  1. 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
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  1. Chalasani, N., Vuppalanchi, R., Rinella, M., Middleton, M. S., Siddiqui, M. S., Barritt, A. S., Kolterman, O., Flores, O., Alonso, C., Iruarrizaga-Lejarreta, M., Gil-Redondo, R., Sirlin, C. B., Zemel, M. B. (2018). Randomised clinical trial: a leucine-metformin-sildenafil combination (NS-0200) vs placebo in patients with non-alcoholic fatty liver disease. Alimentary pharmacology & therapeutics, 47(12), 1639-1651. 
  1. Banerjee J, Bruckbauer A, Zemel MB. 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. 2016;65:1-13 
  1. Niswender K, Kolterman O, Kosinski M, Zemel MB. The effects of leucine-metformin combinations on glycemic control in type 2 diabetes. Diabetes. 2016;65:1144. 
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  1. 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
  1. Wilkinson, DJ et al. Effects of leucine and its metabolite beta-hydroxy-beta-methylbutyrateonhumanskeletalmuscleproteinmetabolism.J.Physiol.2013,591,2911-2923. 
  1. 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 
  1. 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 
  1. 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
  1. NutraIngredients-USA.com, December 17, 2017. Nathan Gray. Could dropping specific amino acids from diet be key to weight loss? 
  1. 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 
  1. 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. 
  1. 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.
  1. Kate Samardzic, Kenneth J. Rodgers. Cytotoxicity and mitochondrial dysfunction caused by the dietary supplement l-norvaline. Toxicology in Vitro, 2019; 56: 163 DOI: 10.1016/j.tiv.2019.01.020 
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  1. 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 
  1. 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.
  1. 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. 
  1. 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.
  1. Yoon M-S. The emerging role of branched-chain amino acids in insulin resistance and metabolism. Forum Nutr 2016; 8: 405-17. 
  1. 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. 
  1. 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 
  1. 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. 
  1. 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 
  1. 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 
  1. 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 
  1. 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.
  1. 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 
  1. 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 
  1. 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. 
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