Leucine

• How It Works

  Leucine is an essential amino acid required for muscle growth and maintenance.

  Leucine is an amino acid that is not made in the human body and is required for muscle maintenance. Therefore, it has to be obtained through dietary sources rich in protein such as dairy, soy, and meats. Leucine is also available as a dietary supplement and is used to improve muscle strength and endurance.

  Studies evaluating leucine suggest it may be useful in some populations to prevent or treat loss of skeletal muscle mass and strength, known as sarcopenia. Leucine can also increase insulin secretion, but does not improve sugar levels in diabetic patients.

• Purported Uses
  • Muscle strength and endurance
    Some studies show that leucine improves muscle strength and endurance.
  • Diabetes
    In a clinical study, leucine did not affect blood sugar levels in diabetic men. Further research is needed.
  • Sarcopenia
    Leucine may be useful in some populations to prevent or treat loss of skeletal muscle mass and strength. More studies are needed as results are mixed across various populations including the frail, elderly, obese, and critically ill patients.
• Do Not Take If
  • You are taking insulin and other antidiabetic medications: Leucine can stimulate insulin secretion and may further lower blood glucose levels.
  • You have maple syrup urine disease: Leucine can accumulate in blood or urine resulting in dysfunction of nerve cells.
  • You are taking phosphodiesterase 5 (PDE5) inhibitors (sildenafil): In animal studies, leucine increased the effects of these drugs. But clinical significance is not known.
• Side Effects

   

  • May lower blood glucose levels
  • May cause vitamin B3 and vitamin B6 deficiencies with excessive intake

   

• Scientific Name

  2-Amino-4-methylpentanoic acid

• Clinical Summary

  Leucine is an essential amino acid that is not synthesized in the human body, and must be obtained from food consisting of plant or animal protein. It is often used together with valine and isoleucine (branched-chain amino acids or BCAA), in parenteral forms for nutritional support to maintain nitrogen balance, and to treat cirrhosis and hepatic encephalopathy. Purified leucine is marketed as a dietary supplement for body building. It is thought to stimulate protein synthesis by activating the mammalian target of rapamycin (mTOR) pathway ^(1) (2). In various animal models, leucine supplementation improved leptin sensitivity ^(18) (19), lipid and glucose metabolism ⁽¹⁹⁾, exercise tolerance ⁽²⁰⁾ , acquired growth hormone resistance ⁽²¹⁾, disease-related skeletal muscle dysfunctions ⁽²²⁾, and anemia ⁽²³⁾.

  In clinical studies, an oral leucine-enriched BCAA mixture increased muscle protein synthesis and reversed sarcopenic processes in cirrhotic patients ⁽²⁴⁾. But supplementation did not have additional effects on exercise capacity, muscle mass or quality of life when compared with supplementation plus exercise ⁽²⁵⁾. Leucine was also found ineffective in improving cerebral blood flow in patients with hepatic encephalopathy ⁽⁴⁴⁾.

  In older adults, taking leucine with daily meals improved integrated myofibrillar protein synthesis in older men, and was equally effective in those with daily protein intake greater than or equal to the RDA ⁽⁴⁵⁾. A leucine-rich essential amino acid mixture along with exercise significantly improved muscle mass and strength, as well as walking speed in community-dwelling sarcopenic women ⁽²⁶⁾; and leucine-enriched supplements improved sarcopenia in older and older-obese adults ^(27) (28). In another study, combining resistance training with high-dose supplementation exerted moderate benefits on muscle strength and functional status ⁽²⁹⁾. But according to a systematic review, although supplementation helps improve body weight, body mass index, and lean body mass, it does not enhance muscle strength in older sarcopenia-prone individuals ⁽³²⁾. Additional studies have shown that leucine does not affect glycemic control in elderly diabetic men ⁽⁵⁾, although in healthy subjects and in the presence of glucose, it stimulates insulin secretion and lowered blood glucose levels ⁽⁸⁾. A review concluded that central leucine injection decreases food intake, but this effect was not reproducible with oral leucine ⁽³³⁾.

  In athletes, dietary supplementation with leucine may improve performance ⁽³⁾ and upper body strength ⁽⁴⁾. However, randomized trials in younger active populations, one involving resistance training along with powdered leucine/protein shakes ⁽³⁰⁾; and another evaluating a post-surgical rehabilitation program along with supplementation among athletes ⁽³¹⁾ failed to find improvements attributable to leucine, although it appeared to promote thigh muscle recovery in the latter study ⁽³¹⁾. Studies in untrained young males reported that supplementation with resistance training does not confer any added benefits in increasing whole-body skeletal muscle mass or strength ⁽⁴⁶⁾; and does not increase muscle strength or cross-sectional area during resistance training ⁽⁴⁷⁾

  Preliminary findings suggest that essential amino acids with high levels of leucine may help prevent muscle loss in patients with non small-cell lung cancer ⁽⁴⁸⁾.

• Food Sources

  Plant and animal proteins

• Purported Uses
  • Muscle strength
  • Endurance
  • Diabetes
  • Sarcopenia
• Mechanism of Action

  Leucine is an essential branched-chain amino acid (BCAA) associated with skeletal muscle growth and maintenance, energy production, and generation of neurotransmitter and gluconeogenic precursors ⁽³⁵⁾. It stimulates protein synthesis by activating the mammalian target of rapamycin (mTOR) pathway ⁽¹⁾, and is thought to enhance muscle anabolic signaling ⁽¹¹⁾.

  Animal models indicate that BCAA metabolism-related gene expression is regulated during adipocyte differentiation and influenced by nutrient levels, and leucine supplementation induces Bcat2 and Bckdha genes during early and late differentiation ⁽³⁵⁾. It was shown to improve insulin sensitivity in mice that were fed a high-fat diet by decreasing adiposity, rather than through direct action on peripheral target organs ⁽³⁶⁾. Supplementation also improved lipid and glucose metabolism and restored leptin sensitivity in previously obese animals ⁽¹⁹⁾. However, in already-obese rats, leucine worsened adiposity by encouraging hypothalamic gene expression that favored fat accumulation ⁽³⁷⁾. In another study, it did not reduce food intake or induce an anorectic pattern of hypothalamic gene expression ⁽³⁸⁾. Co-ingesting leucine and glycine markedly attenuated glucose response, with only a modest increase in insulin response, suggesting their effects on glucose metabolism are partially insulin-independent ⁽³⁹⁾. Leucine along with sub-therapeutic levels of a PDE5 inhibitor altered lipid metabolism from storage to oxidation, improved glycemic control, and reversed hepatic steatosis induced by high-fat feeding ⁽⁴⁰⁾.

  Leucine supplementation speeds connective tissue repair and muscle regeneration by attenuating transforming growth factor-beta type I receptor and activating Smad2/3 ⁽⁴¹⁾. Anti-atrophic effects were not mediated by its metabolite, beta-hydroxy-beta-methyl butyrate, and did not occur in dexamethasone-treated rats ⁽⁴²⁾.

  The ability of leucine to improve anemia in ribosomal protein-deficient cells occurs independently of TP53 ⁽²³⁾. In Diamond-Blackfan anemia patients, leucine modulated protein synthesis by enhancing translation leading to improved hemoglobin levels ⁽⁷⁾. In the skeletal muscle of cirrhotic patients, an oral leucine-enriched BCAA mixture increased autophagy and reversed impaired mTOR1 signaling ⁽²⁴⁾. Leucine may have a protective role in attenuating macrophage foam-cell formation, a hallmark of early atherogenesis, via mechanisms related to the metabolism of cholesterol, triglycerides, and energy production ⁽⁴⁹⁾.

• Contraindications
  • Patients with maple syrup urine disease should not consume leucine and other branched-chain amino acids as they can accumulate in blood or urine causing neuronal dysfunction ⁽¹⁵⁾.
• Adverse Reactions
  • May lower blood glucose levels ⁽⁸⁾.
  • Excessive intake of dietary leucine may cause vitamin B3 and B6 deficiencies ^(9) (10).
• Herb-Drug Interactions
  • Insulin and other antidiabetic medications: Leucine can stimulate insulin secretion and may have additive hypoglycemic effects ^(8) (43).
  • Vitamin B3 and vitamin B6: Leucine can interfere with synthesis of these vitamins ^(9) (10).
  • Phosphodiesterase 5 (PDE5) inhibitors (sildenafil): Animal models indicate leucine may have synergistic effects ⁽⁴⁰⁾. Clinical relevance is not known.
• Herb Lab Interactions
  • Insulin and other antidiabetic medications: Leucine can stimulate insulin secretion and may have additive hypoglycemic effects ^(8) (43).
  • Vitamin B3 and vitamin B6: Leucine can interfere with synthesis of these vitamins ^(9) (10).
  • Phosphodiesterase 5 (PDE5) inhibitors (sildenafil): Animal models indicate leucine may have synergistic effects ⁽⁴⁰⁾. Clinical relevance is not known.
• References

  1. Dreyer HC, Drummond MJ, Pennings B, et al. Leucine-enriched essential amino acid and carbohydrate ingestion following resistance exercise enhances mTOR signaling and protein synthesis in human muscle. Am J Physiol Endocrinol Metab. Feb 2008;294(2):E392-400.

  2. Pasiakos SM, McClung HL, McClung JP, et al. Leucine-enriched essential amino acid supplementation during moderate steady state exercise enhances postexercise muscle protein synthesis. Am J Clin Nutr. Sep 2011;94(3):809-818.

  3. Thomson JS, Ali A, Rowlands DS. Leucine-protein supplemented recovery feeding enhances subsequent cycling performance in well-trained men. Appl Physiol Nutr Metab. Apr 2011;36(2):242-253.

  4. Crowe MJ, Weatherson JN, Bowden BF. Effects of dietary leucine supplementation on exercise performance. Eur J Appl Physiol. Aug 2006;97(6):664-672.

  5. Leenders M, Verdijk LB, van der Hoeven L, et al. Prolonged leucine supplementation does not augment muscle mass or affect glycemic control in elderly type 2 diabetic men. J Nutr. Jun 2011;141(6):1070-1076.

  6. Virgilio M. Treatment of Zebrafish Models of Ribosomopathies (Diamond Blackfan Anemia (DBA) and 5q- Syndrome) with L-Leucine Results In An Improvement of Anemia and Developmental Defects: Evidence for a Common Pathway? Paper presented at: American Society of Hematology Annual Meeting2010; Orange County Convention Center.

  7. Jaako P. Bone Marrow Failure in RPS19-Deficient Mice Is Partly Caused by p53 Activation and Responds to L-Leucine Treatment. Paper presented at: American Society of Hematology Annual Meeting2011; San Diego Convention Center.

  8. Kalogeropoulou D, Lafave L, Schweim K, et al. Leucine, when ingested with glucose, synergistically stimulates insulin secretion and lowers blood glucose. Metabolism. Dec 2008;57(12):1747-1752.

  9. Bender DA. Effects of a dietary excess of leucine on the metabolism of tryptophan in the rat: a mechanism for the pellagragenic action of leucine. Br J Nutr. Jul 1983;50(1):25-32.

  10. Bapurao S, Krishnaswamy K. Vitamin B6 nutritional status of pellagrins and their leucine tolerance. Am J Clin Nutr. May 1978;31(5):819-824.

  11. Glynn EL, Fry CS, Drummond MJ, et al. Excess leucine intake enhances muscle anabolic signaling but not net protein anabolism in young men and women. J Nutr. Nov 2010;140(11):1970-1976.

  12. Cortiella J, Matthews DE, Hoerr RA, et al. Leucine kinetics at graded intakes in young men: quantitative fate of dietary leucine. Am J Clin Nutr. Oct 1988;48(4):998-1009.

  13. Yudkoff M, Daikhin Y, Nissim I, et al. Brain amino acid requirements and toxicity: the example of leucine. J Nutr. Jun 2005;135(6 Suppl):1531S-1538S.

  14. Yudkoff M, Daikhin Y, Grunstein L, et al. Astrocyte leucine metabolism: significance of branched-chain amino acid transamination. J Neurochem. Jan 1996;66(1):378-385.

  15. Kasinski A, Doering CB, Danner DJ. Leucine toxicity in a neuronal cell model with inhibited branched chain amino acid catabolism. Brain Res Mol Brain Res. Mar 30 2004;122(2):180-187.

  16. van Loon LJ. Leucine as a pharmaconutrient in health and disease. Curr Opin Clin Nutr Metab Care. 2012 Jan;15(1):71-7.

  17. Pencharz PB, Elango R, Ball RO. Determination of the tolerable upper intake level of leucine in adult men. J Nutr. 2012 Dec;142(12):2220S-4S.

  18. Yuan XW, Han SF, Zhang JW, et al. Leucine supplementation improves leptin sensitivity in high-fat diet fed rats. Food Nutr Res. 2015;59:27373.

  19. Binder E, Bermudez-Silva FJ, Elie M, et al. Leucine supplementation modulates fuel substrates utilization and glucose metabolism in previously obese mice. Obesity (Silver Spring). Mar 2014;22(3):713-720.

  20. de Moraes WM, Melara TP, de Souza PR, et al. Impact of leucine supplementation on exercise training induced anti-cardiac remodeling effect in heart failure mice. Nutrients. May 2015;7(5):3751-3766.

  21. Gao X, Tian F, Wang X, et al. Leucine supplementation improves acquired growth hormone resistance in rats with protein-energy malnutrition. PLoS One. 2015;10(4):e0125023.

  22. Shemesh A, Wang Y, Yang Y, et al. Suppression of mTORC1 activation in acid-alpha-glucosidase-deficient cells and mice is ameliorated by leucine supplementation. Am J Physiol Regul Integr Comp Physiol. Nov 15 2014;307(10):R1251-1259.

  23. Narla A, Payne EM, Abayasekara N, et al. L-Leucine improves the anaemia in models of Diamond Blackfan anaemia and the 5q- syndrome in a TP53-independent way. Br J Haematol. Nov 2014;167(4):524-528.

  24. Tsien C, Davuluri G, Singh D, et al. Metabolic and molecular responses to leucine-enriched branched chain amino acid supplementation in the skeletal muscle of alcoholic cirrhosis. Hepatology. Jun 2015;61(6):2018-2029.

  25. Roman E, Torrades MT, Nadal MJ, et al. Randomized pilot study: effects of an exercise programme and leucine supplementation in patients with cirrhosis. Dig Dis Sci. Aug 2014;59(8):1966-1975.

  26. Kim HK, Suzuki T, Saito K, et al. Effects of exercise and amino acid supplementation on body composition and physical function in community-dwelling elderly Japanese sarcopenic women: a randomized controlled trial. J Am Geriatr Soc. Jan 2012;60(1):16-23.

  27. Bauer JM, Verlaan S, Bautmans I, et al. Effects of a Vitamin D and Leucine-Enriched Whey Protein Nutritional Supplement on Measures of Sarcopenia in Older Adults, the PROVIDE Study: A Randomized, Double-Blind, Placebo-Controlled Trial. J Am Med Dir Assoc. Jul 10 2015.

  28. Verreijen AM, Verlaan S, Engberink MF, et al. A high whey protein-, leucine-, and vitamin D-enriched supplement preserves muscle mass during intentional weight loss in obese older adults: a double-blind randomized controlled trial. Am J Clin Nutr. Feb 2015;101(2):279-286.

  29. Trabal J, Forga M, Leyes P, et al. Effects of free leucine supplementation and resistance training on muscle strength and functional status in older adults: a randomized controlled trial. Clin Interv Aging. 2015;10:713-723.

  30. Herda AA, Herda TJ, Costa PB, et al. Muscle performance, size, and safety responses after eight weeks of resistance training and protein supplementation: a randomized, double-blinded, placebo-controlled clinical trial. J Strength Cond Res. Nov 2013;27(11):3091-3100.

  31. Laboute E, France J, Trouve P, et al. Rehabilitation and leucine supplementation as possible contributors to an athlete’s muscle strength in the reathletization phase following anterior cruciate ligament surgery. Ann Phys Rehabil Med. Mar 2013;56(2):102-112.

  32. Komar B, Schwingshackl L, Hoffmann G. Effects of leucine-rich protein supplements on anthropometric parameter and muscle strength in the elderly: a systematic review and meta-analysis. J Nutr Health Aging. Apr 2015;19(4):437-446.

  33. Pedroso JA, Zampieri TT, Donato J, Jr. Reviewing the Effects of L-Leucine Supplementation in the Regulation of Food Intake, Energy Balance, and Glucose Homeostasis. Nutrients. May 2015;7(5):3914-3937.

  34. Liu KA, Lashinger LM, Rasmussen AJ, et al. Leucine supplementation differentially enhances pancreatic cancer growth in lean and overweight mice. Cancer Metab. 2014;2(1):6.

  35. Kitsy A, Carney S, Vivar JC, et al. Effects of leucine supplementation and serum withdrawal on branched-chain amino acid pathway gene and protein expression in mouse adipocytes. PLoS One. 2014;9(7):e102615.

  36. Binder E, Bermudez-Silva FJ, Andre C, et al. Leucine supplementation protects from insulin resistance by regulating adiposity levels. PLoS One. 2013;8(9):e74705.

  37. Zampieri TT, Torres-Leal FL, Campana AB, et al. L-leucine supplementation worsens the adiposity of already obese rats by promoting a hypothalamic pattern of gene expression that favors fat accumulation. Nutrients. Apr 2014;6(4):1364-1373.

  38. Zampieri TT, Pedroso JA, Furigo IC, et al. Oral leucine supplementation is sensed by the brain but neither reduces food intake nor induces an anorectic pattern of gene expression in the hypothalamus. PLoS One. 2013;8(12):e84094.

  39. Iverson JF, Gannon MC, Nuttall FQ. Interaction of ingested leucine with glycine on insulin and glucose concentrations. J Amino Acids. 2014;2014:521941.

  40. Fu L, Li F, Bruckbauer A, et al. Interaction between leucine and phosphodiesterase 5 inhibition in modulating insulin sensitivity and lipid metabolism. Diabetes Metab Syndr Obes. 2015;8:227-239.

  41. Pereira MG, Silva MT, Carlassara EO, et al. Leucine supplementation accelerates connective tissue repair of injured tibialis anterior muscle. Nutrients. Oct 2014;6(10):3981-4001.

  42. Baptista IL, Silva WJ, Artioli GG, et al. Leucine and HMB differentially modulate proteasome system in skeletal muscle under different sarcopenic conditions. PLoS One. 2013;8(10):e76752.

  43. Fu L, Bruckbauer A, Li F, et al. Interaction between metformin and leucine in reducing hyperlipidemia and hepatic lipid accumulation in diet-induced obese mice. Metabolism. Jul 17 2015.

  44. Romeiro FG, Ietsugu MDV, Franzoni LC, et al. Which of the branched-chain amino acids increases cerebral blood flow in hepatic encephalopathy? A double-blind randomized trial. Neuroimage Clin. 2018 Mar 28;19:302-310.

  45. Murphy CH, Saddler NI, Devries MC, et al. Leucine supplementation enhances integrative myofibrillar protein synthesis in free-living older men consuming lower- and higher-protein diets: a parallel-group crossover study. Am J Clin Nutr. 2016 Dec;104(6):1594-1606.

  46. Mobley CB, Haun CT, Roberson PA, et al. Effects of Whey, Soy or Leucine Supplementation with 12 Weeks of Resistance Training on Strength, Body Composition, and Skeletal Muscle and Adipose Tissue Histological Attributes in College-Aged Males. Nutrients. 2017 Sep 4;9(9). pii: E972.

  47. Aguiar AF, Grala AP, da Silva RA, et al. Free leucine supplementation during an 8-week resistance training program does not increase muscle mass and strength in untrained young adult subjects. Amino Acids. 2017 Jul;49(7):1255-1262.

  48. Engelen MP, Safar AM, Bartter T, Koeman F, Deutz NE. High anabolic potential of essential amino acid mixtures in advanced nonsmall cell lung cancer. Ann Oncol. 2015 Sep;26(9):1960-6.

  49. Grajeda-Iglesias C, Rom O, Hamoud S, et al. Leucine supplementation attenuates macrophage foam-cell formation: Studies in humans, mice, and cultured macrophages. Biofactors. 2018 May;44(3):245-262.