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Branched Chain Amino Acids in Metabolic Disease

  • Pathogenesis of Type 2 Diabetes and Insulin Resistance (M-E Patti, Section Editor)
  • Published:
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Abstract

Purpose of Review

Elevations in circulating branched chain amino acids (BCAAs) have gained attention as potential contributors to the development of insulin resistance and diabetes.

Recent Findings

Epidemiological evidence strongly supports this conclusion. Suppression of BCAA catabolism in adipose and hepatic tissues appears to be the primary drivers of plasma BCAA elevations. BCAA catabolism may be shunted to skeletal muscle, where it indirectly leads to FA accumulation and insulin resistance, via a number of proposed mechanisms.

Summary

BCAAs have an important role in the development of IR, but our understanding of how plasma BCAA elevations occur, and how these elevations lead to insulin resistance, is still limited.

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References

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  1. Harper AE, Miller RH, Block KP. Branched-chain amino acid metabolism. Annu Rev Nutr. 1984;4:409–54.

    Article  CAS  PubMed  Google Scholar 

  2. Ichihara A, Koyama E. Transaminase of branched chain amino acids. I. Branched chain amino acids-alpha-ketoglutarate transaminase. J Biochem. 1966;59(2):160–9.

    Article  CAS  PubMed  Google Scholar 

  3. Paxton R, Harris RA. Isolation of rabbit liver branched chain alpha-ketoacid dehydrogenase and regulation by phosphorylation. J Biol Chem. 1982;257(23):14433–9.

    CAS  PubMed  Google Scholar 

  4. Harris RA, Popov KM, Shimomura Y, Zhao Y, Jaskiewicz J, Nanaumi N, et al. Purification, characterization, regulation and molecular cloning of mitochondrial protein kinases. Adv Enzym Regul. 1992;32:267–84.

    Article  CAS  Google Scholar 

  5. Damuni Z, Reed LJ. Purification and properties of the catalytic subunit of the branched-chain alpha-keto acid dehydrogenase phosphatase from bovine kidney mitochondria. J Biol Chem. 1987;262(11):5129–32.

    CAS  PubMed  Google Scholar 

  6. Lu G, Sun H, She P, Youn JY, Warburton S, Ping P, et al. Protein phosphatase 2Cm is a critical regulator of branched-chain amino acid catabolism in mice and cultured cells. J Clin Invest. 2009;119(6):1678–87.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Adibi SA. Influence of dietary deprivations on plasma concentration of free amino acids of man. J Appl Physiol. 1968;25(1):52–7.

    Article  CAS  PubMed  Google Scholar 

  8. Felig P, Marliss E, Cahill GF Jr. Plasma amino acid levels and insulin secretion in obesity. N Engl J Med. 1969;281(15):811–6.

    Article  CAS  PubMed  Google Scholar 

  9. Guasch-Ferre M, Hruby A, Toledo E, Clish CB, Martinez-Gonzalez MA, Salas-Salvado J, et al. Metabolomics in prediabetes and diabetes: a systematic review and meta-analysis. Diabetes Care. 2016;39(5):833–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Wurtz P, Soininen P, Kangas AJ, Ronnemaa T, Lehtimaki T, Kahonen M, et al. Branched-chain and aromatic amino acids are predictors of insulin resistance in young adults. Diabetes Care. 2013;36(3):648–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Newgard CB, An J, Bain JR, Muehlbauer MJ, Stevens RD, Lien LF, 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(4):311–26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Walford GA, Ma Y, Clish C, Florez JC, Wang TJ, Gerszten RE, et al. Metabolite profiles of diabetes incidence and intervention response in the diabetes prevention program. Diabetes. 2016;65(5):1424–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Huffman KM, Shah SH, Stevens RD, Bain JR, Muehlbauer M, Slentz CA, et al. Relationships between circulating metabolic intermediates and insulin action in overweight to obese, inactive men and women. Diabetes Care. 2009;32(9):1678–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Tai ES, Tan ML, Stevens RD, Low YL, Muehlbauer MJ, Goh DL, et al. Insulin resistance is associated with a metabolic profile of altered protein metabolism in Chinese and Asian-Indian men. Diabetologia. 2010;53(4):757–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Palmer ND, Stevens RD, Antinozzi PA, Anderson A, Bergman RN, Wagenknecht LE, et al. Metabolomic profile associated with insulin resistance and conversion to diabetes in the insulin resistance atherosclerosis study. J Clin Endocrinol Metab. 2015;100(3):E463–8.

    Article  CAS  PubMed  Google Scholar 

  16. Shah SH, Crosslin DR, Haynes CS, Nelson S, Turer CB, Stevens RD, et al. Branched-chain amino acid levels are associated with improvement in insulin resistance with weight loss. Diabetologia. 2012;55(2):321–30.

    Article  CAS  PubMed  Google Scholar 

  17. Perng W, Gillman MW, Fleisch AF, Michalek RD, Watkins SM, Isganaitis E, et al. Metabolomic profiles and childhood obesity. Obesity (Silver Spring). 2014;22(12):2570–8.

    CAS  Google Scholar 

  18. Krebs M, Brehm A, Krssak M, Anderwald C, Bernroider E, Nowotny P, et al. Direct and indirect effects of amino acids on hepatic glucose metabolism in humans. Diabetologia. 2003;46(7):917–25.

    Article  CAS  PubMed  Google Scholar 

  19. Krebs M, Krssak M, Bernroider E, Anderwald C, Brehm A, Meyerspeer M, et al. Mechanism of amino acid-induced skeletal muscle insulin resistance in humans. Diabetes. 2002;51(3):599–605.

    Article  CAS  PubMed  Google Scholar 

  20. Tremblay F, Krebs M, Dombrowski L, Brehm A, Bernroider E, Roth E, et al. Overactivation of S6 kinase 1 as a cause of human insulin resistance during increased amino acid availability. Diabetes. 2005;54(9):2674–84.

    Article  CAS  PubMed  Google Scholar 

  21. Harris LLS, Smith GI, Patterson BW, Ramaswamy RS, Okunade AL, Kelly SC, et al. Alterations in 3-Hydroxyisobutyrate and FGF21 metabolism are associated with protein ingestion-induced insulin resistance. Diabetes. 2017;66(7):1871–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. • White PJ, Lapworth AL, An J, Wang L, RW MG, Stevens RD, et al. Branched-chain amino acid restriction in Zucker-fatty rats improves muscle insulin sensitivity by enhancing efficiency of fatty acid oxidation and acyl-glycine export. Mol Metab. 2016;5(7):538–51. This study demonstrated that dietary restriction of BCAAs promotes insulin sensitivity.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Fontana L, Cummings NE, Arriola Apelo SI, Neuman JC, Kasza I, Schmidt BA, et al. Decreased consumption of branched-chain amino acids improves metabolic health. Cell Rep. 2016;16(2):520–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Cummings NE, Williams EM, Kasza I, Konon EN, Schaid MD, Schmidt BA, et al. Restoration of metabolic health by decreased consumption of branched-chain amino acids. J Physiol. 2018;596(4):623–45.

    Article  CAS  PubMed  Google Scholar 

  25. • Jang C, Oh SF, Wada S, Rowe GC, Liu L, Chan MC, et al. A branched-chain amino acid metabolite drives vascular fatty acid transport and causes insulin resistance. Nat Med. 2016;22(4):421–6. This study proposes a novel mechanism whereby excess BCAA catabolism in muscle leads to the secretion of signaling metabolites that promote fatty acid influx into muscle, leading to lipotoxicity and insulin resistance.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Wang TJ, Larson MG, Vasan RS, Cheng S, Rhee EP, McCabe E, et al. Metabolite profiles and the risk of developing diabetes. Nat Med. 2011;17(4):448–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Liu J, Semiz S, van der Lee SJ, van der Spek A, Verhoeven A, van Klinken JB, et al. Metabolomics based markers predict type 2 diabetes in a 14-year follow-up study. Metabolomics. 2017;13(9):104.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Merino J, Leong A, Liu CT, Porneala B, Walford GA, von Grotthuss M, et al. Metabolomics insights into early type 2 diabetes pathogenesis and detection in individuals with normal fasting glucose. Diabetologia. 2018;61(6):1315–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Lotta LA, Scott RA, Sharp SJ, Burgess S, Luan J, Tillin T, et al. Genetic predisposition to an impaired metabolism of the branched-chain amino acids and risk of type 2 diabetes: a Mendelian randomisation analysis. PLoS Med. 2016;13(11):e1002179.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Mahendran Y, Jonsson A, Have CT, Allin KH, Witte DR, Jorgensen ME, et al. Genetic evidence of a causal effect of insulin resistance on branched-chain amino acid levels. Diabetologia. 2017;60(5):873–8.

    Article  CAS  PubMed  Google Scholar 

  31. Wang Q, Holmes MV, Davey Smith G, Ala-Korpela M. Genetic support for a causal role of insulin resistance on circulating branched-chain amino acids and inflammation. Diabetes Care. 2017;40(12):1779–86.

    Article  PubMed  Google Scholar 

  32. •• White PJ, RW MG, Grimsrud PA, Tso SC, Yang WH, Haldeman JM, et al. The BCKDH kinase and phosphatase integrate BCAA and lipid metabolism via regulation of ATP-citrate lyase. Cell Metab. 2018;27(6):1281–93 e7. This study demonstrates that lowering BCAAs pharmaceutically can improve insulin resistance. The study also identifies regulation of BCKDK by carbohydrate signaling, and ACLY as a novel target of BCKDK, thereby integrating BCAA, lipid, and carbohydrate metabolism in the liver.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Brosnan JT, Brosnan ME. Branched-chain amino acids: enzyme and substrate regulation. J Nutr. 2006;136(1 Suppl):207S–11S.

    Article  CAS  PubMed  Google Scholar 

  34. •• Neinast MA, Jang C, Hui S, Murashige DS, Chu Q, Morscher RJ, et al. Whole-body metabolic fate of branched chain amino acids in health and insulin resistance. Cell Metab. 2018; in revision. This study provides an integrated and comprehensive description of whole-body BCAA catabolism, using steady-state heavy isotope infusion studies.

  35. Herman MA, She P, Peroni OD, Lynch CJ, Kahn BB. Adipose tissue branched chain amino acid (BCAA) metabolism modulates circulating BCAA levels. J Biol Chem. 2010;285(15):11348–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Hsiao G, Chapman J, Ofrecio JM, Wilkes J, Resnik JL, Thapar D, et al. Multi-tissue, selective PPARgamma modulation of insulin sensitivity and metabolic pathways in obese rats. Am J Physiol Endocrinol Metab. 2011;300(1):E164–74.

    Article  PubMed  Google Scholar 

  37. Pietilainen KH, Naukkarinen J, Rissanen A, Saharinen J, Ellonen P, Keranen H, et al. Global transcript profiles of fat in monozygotic twins discordant for BMI: pathways behind acquired obesity. PLoS Med. 2008;5(3):e51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Wiklund P, Zhang X, Pekkala S, Autio R, Kong L, Yang Y, et al. Insulin resistance is associated with altered amino acid metabolism and adipose tissue dysfunction in normoglycemic women. Sci Rep. 2016;6:24540.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. She P, Van Horn C, Reid T, Hutson SM, Cooney RN, Lynch CJ. Obesity-related elevations in plasma leucine are associated with alterations in enzymes involved in branched-chain amino acid metabolism. Am J Physiol Endocrinol Metab. 2007;293(6):E1552–63.

    Article  CAS  PubMed  Google Scholar 

  40. Lips MA, Van Klinken JB, van Harmelen V, Dharuri HK, t Hoen PA, Laros JF, et al. Roux-en-Y gastric bypass surgery, but not calorie restriction, reduces plasma branched-chain amino acids in obese women independent of weight loss or the presence of type 2 diabetes. Diabetes Care. 2014;37(12):3150–6.

    Article  CAS  PubMed  Google Scholar 

  41. Burrill JS, Long EK, Reilly B, Deng Y, Armitage IM, Scherer PE, et al. Inflammation and ER stress regulate branched-chain amino acid uptake and metabolism in adipocytes. Mol Endocrinol. 2015;29(3):411–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Lo KA, Labadorf A, Kennedy NJ, Han MS, Yap YS, Matthews B, et al. Analysis of in vitro insulin-resistance models and their physiological relevance to in vivo diet-induced adipose insulin resistance. Cell Rep. 2013;5(1):259–70.

    Article  CAS  PubMed  Google Scholar 

  43. Sears DD, Hsiao G, Hsiao A, Yu JG, Courtney CH, Ofrecio JM, et al. Mechanisms of human insulin resistance and thiazolidinedione-mediated insulin sensitization. Proc Natl Acad Sci U S A. 2009;106(44):18745–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Lian K, Du C, Liu Y, Zhu D, Yan W, Zhang H, et al. Impaired adiponectin signaling contributes to disturbed catabolism of branched-chain amino acids in diabetic mice. Diabetes. 2015;64(1):49–59.

    Article  CAS  PubMed  Google Scholar 

  45. Shin AC, Fasshauer M, Filatova N, Grundell LA, Zielinski E, Zhou JY, et al. Brain insulin lowers circulating BCAA levels by inducing hepatic BCAA catabolism. Cell Metab. 2014;20(5):898–909.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Newgard CB. Interplay between lipids and branched-chain amino acids in development of insulin resistance. Cell Metab. 2012;15(5):606–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Lerin C, Goldfine AB, Boes T, Liu M, Kasif S, Dreyfuss JM, et al. Defects in muscle branched-chain amino acid oxidation contribute to impaired lipid metabolism. Mol Metab. 2016;5(10):926–36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Ridaura VK, Faith JJ, Rey FE, Cheng J, Duncan AE, Kau AL, et al. Gut microbiota from twins discordant for obesity modulate metabolism in mice. Science. 2013;341(6150):1241214.

    Article  CAS  PubMed  Google Scholar 

  49. Pedersen HK, Gudmundsdottir V, Nielsen HB, Hyotylainen T, Nielsen T, Jensen BA, et al. Human gut microbes impact host serum metabolome and insulin sensitivity. Nature. 2016;535(7612):376–81.

    Article  CAS  PubMed  Google Scholar 

  50. Saxton RA, Sabatini DM. mTOR signaling in growth, metabolism, and disease. Cell. 2017;168(6):960–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. • Saxton RA, Knockenhauer KE, Wolfson RL, Chantranupong L, Pacold ME, Wang T, et al. Structural basis for leucine sensing by the Sestrin2-mTORC1 pathway. Science. 2016;351(6268):53–8. This manuscript identified the primary molecular sensor for cytoplasmic leucine.

    Article  CAS  PubMed  Google Scholar 

  52. • Wolfson RL, Chantranupong L, Saxton RA, Shen K, Scaria SM, Cantor JR, et al. Sestrin2 is a leucine sensor for the mTORC1 pathway. Science. 2016;351(6268):43–8. This study and the previous one identify Sestrin2 as the molecular sensor for leucine-mediated activation of mTOR signaling.

    Article  CAS  PubMed  Google Scholar 

  53. Nairizi A, She P, Vary TC, Lynch CJ. Leucine supplementation of drinking water does not alter susceptibility to diet-induced obesity in mice. J Nutr. 2009;139(4):715–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Macotela Y, Emanuelli B, Bang 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(6):e21187.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Guo K, Yu YH, Hou J, Zhang Y. Chronic leucine supplementation improves glycemic control in etiologically distinct mouse models of obesity and diabetes mellitus. Nutr Metab (Lond). 2010;7:57.

    Article  CAS  Google Scholar 

  56. 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. 2015;7(5):3914–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Corkey BE. Banting lecture 2011: hyperinsulinemia: cause or consequence? Diabetes. 2012;61(1):4–13.

    Article  CAS  PubMed  Google Scholar 

  58. Cavaghan MK, Ehrmann DA, Polonsky KS. Interactions between insulin resistance and insulin secretion in the development of glucose intolerance. J Clin Invest. 2000;106(3):329–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Roberts CK, Hevener AL, Barnard RJ. Metabolic syndrome and insulin resistance: underlying causes and modification by exercise training. Compr Physiol. 2013;3(1):1–58.

    PubMed  PubMed Central  Google Scholar 

  60. Wilson DF, Cember ATJ, Matschinsky FM. Glutamate dehydrogenase: role in regulating metabolism and insulin release in pancreatic beta-cells. J Appl Physiol. 1985;2018

  61. Koves TR, Ussher JR, Noland RC, Slentz D, Mosedale M, Ilkayeva O, et al. Mitochondrial overload and incomplete fatty acid oxidation contribute to skeletal muscle insulin resistance. Cell Metab. 2008;7(1):45–56.

    Article  CAS  PubMed  Google Scholar 

  62. Haufe S, Engeli S, Kaminski J, Witt H, Rein D, Kamlage B, et al. Branched-chain amino acid catabolism rather than amino acids plasma concentrations is associated with diet-induced changes in insulin resistance in overweight to obese individuals. Nutr Metab Cardiovasc Dis. 2017;27(10):858–64.

    Article  CAS  PubMed  Google Scholar 

  63. Mardinoglu A, Gogg S, Lotta LA, Stancakova A, Nerstedt A, Boren J, et al. Elevated plasma levels of 3-Hydroxyisobutyric acid are associated with incident type 2 diabetes. EBioMedicine. 2018;27:151–5.

    Article  PubMed  Google Scholar 

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Funding

The authors are supported by grants from the NIH: T32 GM-07229 (MN), and R01 DK107667, DK114103 (ZA).

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  1. Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, TRC 11-106 3400 Civic Blvd, Philadelphia, PA, 19104, USA

    Zoltan Arany & Michael Neinast

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  1. Zoltan Arany
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Correspondence to Zoltan Arany.

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Zolt Arany and Michael Neinast declare that they have no conflict of interest.

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This article is part of the Topical Collection on Pathogenesis of Type 2 Diabetes and Insulin Resistance

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Arany, Z., Neinast, M. Branched Chain Amino Acids in Metabolic Disease. Curr Diab Rep 18, 76 (2018). https://doi.org/10.1007/s11892-018-1048-7

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