Skip to main content

Insulin resistance and the metabolism of branched-chain amino acids

Abstract

Insulin resistance (IR) is a key pathological feature of metabolic syndrome and subsequently causes serious health problems with an increased risk of several common metabolic disorders. IR related metabolic disturbance is not restricted to carbohydrates but impacts global metabolic network. Branched-chain amino acids (BCAAs), namely valine, leucine and isoleucine, are among the nine essential amino acids, accounting for 35% of the essential amino acids in muscle proteins and 40% of the preformed amino acids required by mammals. The BCAAs are particularly responsive to the inhibitory insulin action on amino acid release by skeletal muscle and their metabolism is profoundly altered in insulin resistant conditions and/or insulin deficiency. Although increased circulating BCAA concentration in insulin resistant conditions has been noted for many years and BCAAs have been reported to be involved in the regulation of glucose homeostasis and body weight, it is only recently that BCAAs are found to be closely associated with IR. This review will focus on the recent findings on BCAAs from both epidemic and mechanistic studies.

This is a preview of subscription content, access via your institution.

References

  1. Lewis GF, Carpentier A, Adeli K, Giacca A. Disordered fat storage and mobilization in the pathogenesis of insulin resistance and type 2 diabetes. Endocr Rev 2002; 23(2): 201–229

    PubMed  Article  CAS  Google Scholar 

  2. Grundy SM, Brewer HB Jr, Cleeman JI, Smith SC Jr, Lenfant C. Definition of metabolic syndrome: report of the National Heart, Lung, and Blood Institute/American Heart Association conference on scientific issues related to definition. Arterioscler Thromb Vasc Biol 2004; 24(2): e13–e18

    PubMed  Article  CAS  Google Scholar 

  3. Rader DJ. Effect of insulin resistance, dyslipidemia, and intraabdominal adiposity on the development of cardiovascular disease and diabetes mellitus. Am J Med 2007; 120(3 Suppl 1): S12–S18

    PubMed  Article  CAS  Google Scholar 

  4. World Health Organization. Obesity and overweight: Fact sheet N°311. 2012

    Google Scholar 

  5. American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care 2009; 32(Suppl 1): S62–S67

    Article  Google Scholar 

  6. Layman DK. The role of leucine in weight loss diets and glucose homeostasis. J Nutr 2003; 133(1): 261S–267S

    PubMed  Google Scholar 

  7. Doi M, Yamaoka I, Nakayama M, Mochizuki S, Sugahara K, Yoshizawa F. Isoleucine, a blood glucose-lowering amino acid, increases glucose uptake in rat skeletal muscle in the absence of increases in AMP-activated protein kinase activity. J Nutr 2005; 135(9): 2103–2108

    PubMed  CAS  Google Scholar 

  8. Doi M, Yamaoka I, Nakayama M, Sugahara K, Yoshizawa F. Hypoglycemic effect of isoleucine involves increased muscle glucose uptake and whole body glucose oxidation and decreased hepatic gluconeogenesis. Am J Physiol Endocrinol Metab 2007; 292(6): E1683–E1693

    PubMed  Article  CAS  Google Scholar 

  9. Nishitani S, Takehana K, Fujitani S, Sonaka I. Branched-chain amino acids improve glucose metabolism in rats with liver cirrhosis. Am J Physiol Gastrointest Liver Physiol 2005; 288(6): G1292–G1300

    PubMed  Article  CAS  Google Scholar 

  10. Cota D, Proulx K, Smith KA, Kozma SC, Thomas G, Woods SC, Seeley RJ. Hypothalamic mTOR signaling regulates food intake. Science 2006; 312(5775): 927–930

    PubMed  Article  CAS  Google Scholar 

  11. Baum JI, Layman DK, Freund GG, Rahn KA, Nakamura MT, Yudell BE. A reduced carbohydrate, increased protein diet stabilizes glycemic control and minimizes adipose tissue glucose disposal in rats. J Nutr 2006; 136(7): 1855–1861

    PubMed  CAS  Google Scholar 

  12. Layman DK, Walker DA. Potential importance of leucine in treatment of obesity and the metabolic syndrome. J Nutr 2006; 136(1 Suppl): 319S–323S

    PubMed  CAS  Google Scholar 

  13. Caballero B, Finer N, Wurtman RJ. Plasma amino acids and insulin levels in obesity: response to carbohydrate intake and tryptophan supplements. Metabolism 1988; 37(7): 672–676

    PubMed  Article  CAS  Google Scholar 

  14. Felig P, Marliss E, Cahill GF Jr. Plasma amino acid levels and insulin secretion in obesity. N Engl J Med 1969; 281(15): 811–816

    PubMed  Article  CAS  Google Scholar 

  15. Felig P, Marliss E, Cahill GF Jr. Are plasma amino acid levels elevated in obesity? N Engl J Med 1970; 282(3): 166

    PubMed  CAS  Google Scholar 

  16. Marchesini G, Bianchi G, Rossi B, Muggeo M, Bonora E. Effects of hyperglycaemia and hyperinsulinaemia on plasma amino acid levels in obese subjects with normal glucose tolerance. Int J Obes Relat Metab Disord 2000; 24(5): 552–558

    PubMed  Article  CAS  Google Scholar 

  17. Newgard CB, An J, Bain JR, Muehlbauer MJ, Stevens RD, Lien LF, Haqq AM, Shah SH, Arlotto M, Slentz CA, Rochon J, Gallup D, Ilkayeva O, Wenner BR, Yancy WS Jr, Eisenson H, Musante G, Surwit RS, Millington DS, Butler MD, Svetkey LP. A branchedchain amino acid-related metabolic signature that differentiates obese and lean humans and contributes to insulin resistance. Cell Metab 2009; 9(4): 311–326

    PubMed  Article  CAS  Google Scholar 

  18. Shimomura Y, Honda T, Shiraki M, Murakami T, Sato J, Kobayashi H, Mawatari K, Obayashi M, Harris RA. Branched-chain amino acid catabolism in exercise and liver disease. J Nutr 2006; 136(1 Suppl): 250S–253S

    PubMed  CAS  Google Scholar 

  19. Shimomura Y, Obayashi M, Murakami T, Harris RA. Regulation of Jingyi Lu et al. 57 branched-chain amino acid catabolism: nutritional and hormonal regulation of activity and expression of the branched-chain alphaketo acid dehydrogenase kinase. Curr Opin Clin Nutr Metab Care 2001; 4(5): 419–423

    PubMed  Article  CAS  Google Scholar 

  20. Sweatt AJ, Wood M, Suryawan A, Wallin R, Willingham MC, Hutson SM. Branched-chain amino acid catabolism: unique segregation of pathway enzymes in organ systems and peripheral nerves. Am J Physiol Endocrinol Metab 2004; 286(1): E64–E76

    PubMed  Article  CAS  Google Scholar 

  21. Wei J, Xie G, Ge S, Qiu Y, Liu W, Lu A, Chen T, Li H, Zhou Z, Jia W. Metabolic transformation of DMBA-induced carcinogenesis and inhibitory effect of salvianolic acid b and breviscapine treatment. J Proteome Res 2012; 11(2): 1302–1316

    PubMed  Article  CAS  Google Scholar 

  22. Harris RA, Hawes JW, Popov KM, Zhao Y, Shimomura Y, Sato J, Jaskiewicz J, Hurley TD. Studies on the regulation of the mitochondrial alpha-ketoacid dehydrogenase complexes and their kinases. Adv Enzyme Regul 1997; 37: 271–293

    PubMed  Article  CAS  Google Scholar 

  23. Popov KM, Zhao Y, Shimomura Y, Kuntz MJ, Harris RA. Branched-chain alpha-ketoacid dehydrogenase kinase. Molecular cloning, expression, and sequence similarity with histidine protein kinases. J Biol Chem 1992; 267(19): 13127–13130

    PubMed  CAS  Google Scholar 

  24. 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): 5129–5132

    PubMed  CAS  Google Scholar 

  25. Huffman KM, Shah SH, Stevens RD, Bain JR, Muehlbauer M, Slentz CA, Tanner CJ, Kuchibhatla M, Houmard JA, Newgard CB, Kraus WE. Relationships between circulating metabolic intermediates and insulin action in overweight to obese, inactive men and women. Diabetes Care 2009; 32(9): 1678–1683

    PubMed  Article  CAS  Google Scholar 

  26. Shaham O, Wei R, Wang TJ, Ricciardi C, Lewis GD, Vasan RS, Carr SA, Thadhani R, Gerszten RE, Mootha VK. Metabolic profiling of the human response to a glucose challenge reveals distinct axes of insulin sensitivity. Mol Syst Biol 2008; 4: 214

    PubMed  Article  Google Scholar 

  27. Tai ES, Tan ML, Stevens RD, Low YL, Muehlbauer MJ, Goh DL, Ilkayeva OR, Wenner BR, Bain JR, Lee JJ, Lim SC, Khoo CM, Shah SH, Newgard CB. Insulin resistance is associated with a metabolic profile of altered protein metabolism in Chinese and Asian-Indian men. Diabetologia 2010; 53(4): 757–767

    PubMed  Article  CAS  Google Scholar 

  28. Wang TJ, Larson MG, Vasan RS, Cheng S, Rhee EP, McCabe E, Lewis GD, Fox CS, Jacques PF, Fernandez C, O’Donnell CJ, Carr SA, Mootha VK, Florez JC, Souza A, Melander O, Clish CB, Gerszten RE. Metabolite profiles and the risk of developing diabetes. Nat Med 2011; 17(4): 448–453

    PubMed  Article  Google Scholar 

  29. Floegel A, Stefan N, Yu Z, Muhlenbruch K, Drogan D, Joost HG, Fritsche A, Haring HU, Hrabe de Angelis M, Peters A, Roden M, Prehn C, Wang-Sattler R, Illig T, Schulze MB, Adamski J, Boeing H, Pischon T. Identification of Serum Metabolites Associated With Risk of Type 2 Diabetes Using a Targeted Metabolomic Approach. Diabetes 2012 Oct 4. [Epub ahead of print] doi: 10.2337/db12-0495

  30. Wang-Sattler R, Yu Z, Herder C, Messias AC, Floegel A, He Y, Heim K, Campillos M, Holzapfel C, Thorand B, Grallert H, Xu T, Bader E, Huth C, Mittelstrass K, Döring A, Meisinger C, Gieger C, Prehn C, Roemisch-Margl W, Carstensen M, Xie L, Yamanaka-Okumura H, Xing G, Ceglarek U, Thiery J, Giani G, Lickert H, Lin X, Li Y, Boeing H, Joost HG, de Angelis MH, Rathmann W, Suhre K, Prokisch H, Peters A, Meitinger T, Roden M, Wichmann HE, Pischon T, Adamski J, Illig T. Novel biomarkers for pre-diabetes identified by metabolomics. Mol Syst Biol 2012; 8: 615

    PubMed  Article  CAS  Google Scholar 

  31. McCormack SE, Shaham O, McCarthy MA, Deik AA, Wang TJ, Gerszten RE, Clish CB, Mootha VK, Grinspoon SK, Fleischman A. Circulating branched-chain amino acid concentrations are associated with obesity and future insulin resistance in children and adolescents. Pediatr Obes 2013; 8(1): 52–61

    PubMed  Article  CAS  Google Scholar 

  32. Shah SH, Crosslin DR, Haynes CS, Nelson S, Turer CB, Stevens RD, Muehlbauer MJ, Wenner BR, Bain JR, Laferrère B, Gorroochurn P, Teixeira J, Brantley PJ, Stevens VJ, Hollis JF, Appel LJ, Lien LF, Batch B, Newgard CB, Svetkey LP. Branchedchain amino acid levels are associated with improvement in insulin resistance with weight loss. Diabetologia 2012; 55(2): 321–330

    PubMed  Article  CAS  Google Scholar 

  33. Laferrère B, Reilly D, Arias S, Swerdlow N, Gorroochurn P, Bawa B, Bose M, Teixeira J, Stevens RD, Wenner BR, Bain JR, Muehlbauer MJ, Haqq A, Lien L, Shah SH, Svetkey LP, Newgard CB. Differential metabolic impact of gastric bypass surgery versus dietary intervention in obese diabetic subjects despite identical weight loss. Sci Transl Med 2011; 3(80):80re2

    PubMed  Article  Google Scholar 

  34. Luzi L, Castellino P, DeFronzo RA. Insulin and hyperaminoacidemia regulate by a different mechanism leucine turnover and oxidation in obesity. Am J Physiol 1996; 270(2 Pt 1): E273–E281

    PubMed  CAS  Google Scholar 

  35. Argilés JM, Busquets S, Alvarez B, López-Soriano FJ. Mechanism for the increased skeletal muscle protein degradation in the obese Zucker rat. J Nutr Biochem 1999; 10(4): 244–248

    PubMed  Article  Google Scholar 

  36. Wang X, Hu Z, Hu J, Du J, Mitch WE. Insulin resistance accelerates muscle protein degradation: Activation of the ubiquitin-proteasome pathway by defects in muscle cell signaling. Endocrinology 2006; 147(9): 4160–4168

    PubMed  Article  CAS  Google Scholar 

  37. Suryawan A, Hawes JW, Harris RA, Shimomura Y, Jenkins AE, Hutson SM. A molecular model of human branched-chain amino acid metabolism. Am J Clin Nutr 1998; 68(1): 72–81

    PubMed  CAS  Google Scholar 

  38. She P, Reid TM, Bronson SK, Vary TC, Hajnal A, Lynch CJ, Hutson SM. Disruption of BCATm in mice leads to increased energy expenditure associated with the activation of a futile protein turnover cycle. Cell Metab 2007; 6(3): 181–194

    PubMed  Article  CAS  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–E1563

    PubMed  Article  CAS  Google Scholar 

  40. Pietiläinen KH, Naukkarinen J, Rissanen A, Saharinen J, Ellonen P, Keränen H, Suomalainen A, Götz A, Suortti T, Yki-Järvinen H, Oresic M, Kaprio J, Peltonen L. Global transcript profiles of fat in monozygotic twins discordant for BMI: pathways behind acquired obesity. PLoS Med 2008; 5(3): e51

    PubMed  Article  Google Scholar 

  41. 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): 11348–11356

    PubMed  Article  CAS  Google Scholar 

  42. Hsiao G, Chapman J, Ofrecio JM, Wilkes J, Resnik JL, Thapar D, Subramaniam S, Sears DD. Multi-tissue, selective PPARγ modulation of insulin sensitivity and metabolic pathways in obese rats. Am J Physiol Endocrinol Metab 2011; 300(1): E164–E174

    PubMed  Article  Google Scholar 

  43. Sears DD, Hsiao G, Hsiao A, Yu JG, Courtney CH, Ofrecio JM, Chapman J, Subramaniam S. Mechanisms of human insulin resistance and thiazolidinedione-mediated insulin sensitization. Proc Natl Acad Sci USA 2009; 106(44): 18745–18750

    PubMed  Article  CAS  Google Scholar 

  44. Lefort N, Glancy B, Bowen B, Willis WT, Bailowitz Z, De Filippis EA, Brophy C, Meyer C, Højlund K, Yi Z, Mandarino LJ. Increased reactive oxygen species production and lower abundance of complex I subunits and carnitine palmitoyltransferase 1B protein despite normal mitochondrial respiration in insulin-resistant human skeletal muscle. Diabetes 2010; 59(10): 2444–2452

    PubMed  Article  CAS  Google Scholar 

  45. Hay N, Sonenberg N. Upstream and downstream of mTOR. Genes Dev 2004; 18(16): 1926–1945

    PubMed  Article  CAS  Google Scholar 

  46. Hara K, Maruki Y, Long X, Yoshino K, Oshiro N, Hidayat S, Tokunaga C, Avruch J, Yonezawa K. Raptor, a binding partner of target of rapamycin (TOR), mediates TOR action. Cell 2002; 110(2): 177–189

    PubMed  Article  CAS  Google Scholar 

  47. Haruta T, Uno T, Kawahara J, Takano A, Egawa K, Sharma PM, Olefsky JM, Kobayashi M. A rapamycin-sensitive pathway downregulates insulin signaling via phosphorylation and proteasomal degradation of insulin receptor substrate-1. Mol Endocrinol 2000; 14(6): 783–794

    PubMed  Article  CAS  Google Scholar 

  48. O’Connor JC, Freund GG. Vanadate and rapamycin synergistically enhance insulin-stimulated glucose uptake. Metabolism 2003; 52(6): 666–674

    PubMed  Article  Google Scholar 

  49. Pederson TM, Kramer DL, Rondinone CM. Serine/threonine phosphorylation of IRS-1 triggers its degradation: possible regulation by tyrosine phosphorylation. Diabetes 2001; 50(1): 24–31

    PubMed  Article  CAS  Google Scholar 

  50. Sun XJ, Rothenberg P, Kahn CR, Backer JM, Araki E, Wilden PA, Cahill DA, Goldstein BJ, White MF. Structure of the insulin receptor substrate IRS-1 defines a unique signal transduction protein. Nature 1991; 352(6330): 73–77

    PubMed  Article  CAS  Google Scholar 

  51. Tzatsos A, Kandror KV. Nutrients suppress phosphatidylinositol 3-kinase/Akt signaling via raptor-dependent mTOR-mediated insulin receptor substrate 1 phosphorylation. Mol Cell Biol 2006; 26(1): 63–76

    PubMed  Article  CAS  Google Scholar 

  52. Tremblay F, Krebs M, Dombrowski L, Brehm A, Bernroider E, Roth E, Nowotny P, Waldhäusl W, Marette A, Roden M. Overactivation of S6 kinase 1 as a cause of human insulin resistance during increased amino acid availability. Diabetes 2005; 54(9): 2674–2684

    PubMed  Article  CAS  Google Scholar 

  53. Xiao F, Huang Z, Li H, Yu J, Wang C, Chen S, Meng Q, Cheng Y, Gao X, Li J, Liu Y, Guo F. Leucine deprivation increases hepatic insulin sensitivity via GCN2/mTOR/S6K1 and AMPK pathways. Diabetes 2011; 60(3): 746–756

    PubMed  Article  CAS  Google Scholar 

  54. Bruhat A, Jousse C, Fafournoux P. Amino acid limitation regulates gene expression. Proc Nutr Soc 1999; 58(3): 625–632

    PubMed  Article  CAS  Google Scholar 

  55. Kilberg MS, Pan YX, Chen H, Leung-Pineda V. Nutritional control of gene expression: how mammalian cells respond to amino acid limitation. Annu Rev Nutr 2005; 25(1): 59–85

    PubMed  Article  CAS  Google Scholar 

  56. Guo F, Cavener DR. The GCN2 eIF2alpha kinase regulates fattyacid homeostasis in the liver during deprivation of an essential amino acid. Cell Metab 2007; 5(2): 103–114

    PubMed  Article  CAS  Google Scholar 

  57. Macotela Y, Emanuelli B, Bång AM, Espinoza DO, Boucher J, Beebe K, Gall W, Kahn CR. Dietary leucine-an environmental modifier of insulin resistance acting on multiple levels of metabolism. PLoS ONE 2011; 6(6): e21187

    PubMed  Article  CAS  Google Scholar 

  58. 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(6): 1647–1654

    PubMed  Article  CAS  Google Scholar 

  59. 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): 715–719

    PubMed  Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Wei Jia.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Lu, J., Xie, G., Jia, W. et al. Insulin resistance and the metabolism of branched-chain amino acids. Front. Med. 7, 53–59 (2013). https://doi.org/10.1007/s11684-013-0255-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11684-013-0255-5

Keywords

  • branched-chain amino acids
  • leucine
  • isoleucine
  • valine
  • insulin resistance