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Amino Acids

, Volume 43, Issue 1, pp 171–181 | Cite as

Insulin resistance and the metabolism of branched-chain amino acids in humans

  • María M. AdevaEmail author
  • Jesús Calviño
  • Gema Souto
  • Cristóbal Donapetry
Review Article

Abstract

Peripheral resistance to insulin action is the major mechanism causing the metabolic syndrome and eventually type 2 diabetes mellitus. The metabolic derangement associated with insulin resistance is extensive and not restricted to carbohydrates. The branched-chain amino acids (BCAAs) are particularly responsive to the inhibitory insulin action on amino acid release by skeletal muscle and their metabolism is profoundly altered in conditions featuring insulin resistance, insulin deficiency, or both. Obesity, the metabolic syndrome and diabetes mellitus display a gradual increase in the plasma concentration of BCAAs, from the obesity-related low-grade insulin-resistant state to the severe deficiency of insulin action in diabetes ketoacidosis. Obesity-associated hyperinsulinemia succeeds in maintaining near-normal or slightly elevated plasma concentration of BCAAs, despite the insulin-resistant state. The low circulating levels of insulin and/or the deeper insulin resistance occurring in diabetes mellitus are associated with more marked elevation in the plasma concentration of BCAAs. In diabetes ketoacidosis, the increase in plasma BCAAs is striking, returning to normal when adequate metabolic control is achieved. The metabolism of BCAAs is also disturbed in other situations typically featuring insulin resistance, including kidney and liver dysfunction. However, notwithstanding the insulin-resistant state, the plasma level of BCAAs in these conditions is lower than in healthy subjects, suggesting that these organs are involved in maintaining BCAAs blood concentration. The pathogenesis of the decreased BCAAs plasma level in kidney and liver dysfunction is unclear, but a decreased afflux of these amino acids into the blood stream has been observed.

Keywords

Insulin resistance Branched-chain amino acids Leucine Isoleucine Valine 

Notes

Acknowledgments

There was no financial support for this work.

Conflict of interest

None.

References

  1. Adibi SA (1968) Influence of dietary deprivations on plasma concentration of free amino acids of man. J Appl Physiol 25:52–57PubMedGoogle Scholar
  2. Alvestrand A, Defronzo RA, Smith D et al (1988) Influence of hyperinsulinaemia on intracellular amino acid levels and amino acid exchange across splanchnic and leg tissues in uraemia. Clin Sci (Lond) 74:155–163Google Scholar
  3. Aoki TT, Muller WA, Brennan MF et al (1973) Blood cell and plasma amino acid levels across forearm muscle during a protein meal. Diabetes 22:768–775PubMedGoogle Scholar
  4. Aoki TT, Brennan MF, Müller WA et al (1976) Amino acid levels across normal forearm muscle and splanchnic bed after a protein meal. Am J Clin Nutr 29:340–350PubMedGoogle Scholar
  5. Aoki TT, Brennan MF, Fitzpatrick GF et al (1981) Leucine meal increases glutamine and total nitrogen release from forearm muscle. J Clin Invest 68:1522–1528PubMedCrossRefGoogle Scholar
  6. Berger M, Zimmermann-Telschow H, Berchtold P et al (1978) Blood amine acid levels in patients with insulin excess (functioning insulinoma) and insulin deficiency (diabetic ketosis). Metabolism 27:793–799PubMedCrossRefGoogle Scholar
  7. Bergström J, Alvestrand A, Fürst P (1990) Plasma and muscle free amino acids in maintenance hemodialysis patients without protein malnutrition. Kidney Int 38:108–114PubMedCrossRefGoogle Scholar
  8. Boirie Y, Broyer M, Gagnadoux MF et al (2000) Alterations of protein metabolism by metabolic acidosis in children with chronic renal failure. Kidney Int 58:236–241PubMedCrossRefGoogle Scholar
  9. Caballero B, Wurtman RJ (1991) Differential effects of insulin resistance on leucine and glucose kinetics in obesity. Metabolism 40:51–58PubMedCrossRefGoogle Scholar
  10. Canepa A, Filho JC, Gutierrez A et al (2002) 9 Free amino acids in plasma, red blood cells, polymorphonuclear leukocytes, and muscle in normal and uraemic children. Nephrol Dial Transplant 17:413–421PubMedCrossRefGoogle Scholar
  11. Chang CF, Chou HT, Lin YJ et al (2006) Structure of the subunit binding domain and dynamics of the di-domain region from the core of human branched chain α-ketoacid dehydrogenase complex. J Biol Chem 281:28345–28353PubMedCrossRefGoogle Scholar
  12. Chevalier S, Marliss EB, Morais JA et al (2005) 9 Whole-body protein anabolic response is resistant to the action of insulin in obese women. Am J Clin Nutr 82:355–365PubMedGoogle Scholar
  13. Chevalier S, Burgess SC, Malloy CR et al (2006) The greater contribution of gluconeogenesis to glucose production in obesity is related to increased whole-body protein catabolism. Diabetes 55:675–681PubMedCrossRefGoogle Scholar
  14. Darmaun D, Déchelotte P (1991) Role of leucine as a precursor of glutamine alpha-amino nitrogen in vivo in humans. Am J Physiol 260(2 Pt 1):E326–E329PubMedGoogle Scholar
  15. Deferrari G, Garibotto G, Robaudo C et al (1981) Brain metabolism of amino acids and ammonia in patients with chronic renal insufficiency. Kidney Int 20:505–510PubMedCrossRefGoogle Scholar
  16. Deferrari G, Garibotto G, Robaudo C et al (1985) Leg metabolism of amino acids and ammonia in patients with chronic renal failure. Clin Sci (Lond) 69:143–151Google Scholar
  17. DeFronzo RA, Beckles AD (1979) Glucose intolerance following chronic metabolic acidosis in man. Am J Physiol 236:E328–334PubMedGoogle Scholar
  18. DeFronzo RA, Felig P (1980) Amino acid metabolism in uremia: insights gained from normal and diabetic man. Am J Clin Nutr 33:1378–1386PubMedGoogle Scholar
  19. DeFronzo RA, Alvestrand A, Smith D et al (1981) Insulin resistance in uremia. J Clin Invest 67:563–568PubMedCrossRefGoogle Scholar
  20. Dickinson JM, Rasmussen BB (2010) Essential amino acid sensing, signaling, and transport in the regulation of human muscle protein metabolism. Curr Opin Clin Nutr Metab Care 14:83–88CrossRefGoogle Scholar
  21. Elia M, Livesey G (1983) Effects of ingested steak and infused leucine on forelimb metabolism in man and the fate of the carbon skeletons and amino groups of branched-chain amino acids. Clin Sci (Lond) 64:517–526Google Scholar
  22. Felig P (1975) Amino acid metabolism in man. Annu Rev Biochem 44:933–955PubMedCrossRefGoogle Scholar
  23. Felig P, Marliss E, Cahill GF Jr (1969a) Plasma amino acid levels and insulin secretion in obesity. N Engl J Med 281:811–816PubMedCrossRefGoogle Scholar
  24. Felig P, Owen OE, Wahren J et al (1969b) Amino acid metabolism during prolonged starvation. J Clin Invest 48:584–594PubMedCrossRefGoogle Scholar
  25. Felig P, Wahren J, Hendler R et al (1974) Splanchnic glucose and amino acid metabolism in obesity. J Clin Invest 53:582–590PubMedCrossRefGoogle Scholar
  26. Forlani G, Vannini P, Marchesini G et al (1984) Insulin-dependent metabolism of branched-chain amino acids in obesity. Metabolism 33:147–150PubMedCrossRefGoogle Scholar
  27. Fürst P, Alvestrand A, Bergström J (1992) Branched-chain amino acids and branched-chain ketoacids in uremia. Contrib Nephrol 98:44–58PubMedGoogle Scholar
  28. Garibotto G, Russo R, Sala MR et al (1992) Muscle protein turnover and amino acid metabolism in patients with chronic renal failure. Miner Electrolyte Metab 18(2–5):217–221PubMedGoogle Scholar
  29. Garibotto G, Paoletti E, Fiorini F et al (1993a) Peripheral metabolism of branched-chain keto acids in patients with chronic renal failure. Miner Electrolyte Metab 19:25–31PubMedGoogle Scholar
  30. Garibotto G, Paoletti E, Fiorini F et al (1993b) Peripheral metabolism of branched-chain keto acids in patients with chronic renal failure. Miner Electrolyte Metab 19:25–31PubMedGoogle Scholar
  31. Garibotto G, Russo R, Sofia A et al (1994a) Skeletal muscle protein synthesis and degradation in patients with chronic renal failure. Kidney Int 45:1432–1439PubMedCrossRefGoogle Scholar
  32. Garibotto G, Russo R, Sofia A et al (1994b) Skeletal muscle protein synthesis and degradation in patients with chronic renal failure. Kidney Int 45:1432–1439PubMedCrossRefGoogle Scholar
  33. Garibotto G, Russo R, Sofia A et al (1996) Muscle protein turnover in chronic renal failure patients with metabolic acidosis or normal acid-base balance. Miner Electrolyte Metab 22(1–3):58–61PubMedGoogle Scholar
  34. Garibotto G, Tessari P, Robaudo C et al (1997) Leucine metabolism and protein dynamics in the human kidney. Contrib Nephrol 121:143–148PubMedCrossRefGoogle Scholar
  35. Gelfand RA, Glickman MG, Jacob R et al (1986) Removal of infused amino acids by splanchnic and leg tissues in humans. Am J Physiol 250(4 Pt 1):E407–E413PubMedGoogle Scholar
  36. Goto M, Shinno H, Ichihara A (1977) Isozyme patterns of branched-chain amino acid transaminase in human tissues and tumors. Gann 68:663–667PubMedGoogle Scholar
  37. Graham KA, Reaich D, Channon SM et al (1997) Correction of acidosis in hemodialysis decreases whole-body protein degradation. J Am Soc Nephrol 8:632–637PubMedGoogle Scholar
  38. Hagenfeldt L, Eriksson S, Wahren J (1980) Influence of leucine on arterial concentrations and regional exchange of amino acids in healthy subjects. Clin Sci (Lond) 59:173–181Google Scholar
  39. Hagenfeldt L, Eriksson LS, Wahren J (1983) Amino acids in liver disease. Proc Nutr Soc 42:497–506PubMedCrossRefGoogle Scholar
  40. Haymond MW, Miles JM (1982) Branched chain amino acids as a major source of alanine nitrogen in man. Diabetes 31:86–89PubMedCrossRefGoogle Scholar
  41. Howarth KR, Burgomaster KA, Phillips SM et al (2007) Exercise training increases branched-chain oxoacid dehydrogenase kinase content in human skeletal muscle. Am J Physiol Regul Integr Comp Physiol 293:R1335–R1341PubMedCrossRefGoogle Scholar
  42. Huffman KM, Shah SH, Stevens RD et al (2009) Relationships between circulating metabolic intermediates and insulin action in overweight to obese, inactive men and women. Diabetes Care 32:1678–1683PubMedCrossRefGoogle Scholar
  43. Jones MR, Kopple JD (1978) Valine metabolism in normal and chronically uremic man. Am J Clin Nutr 31:1660–1664PubMedGoogle Scholar
  44. Keller U, Turkalj I, Laager R et al (2002) Effects of medium- and long-chain fatty acids on whole body leucine and glucose kinetics in man. Metabolism 51:754–760PubMedCrossRefGoogle Scholar
  45. Kooman JP, Deutz NE, Zijlmans P et al (1997) The influence of bicarbonate supplementation on plasma levels of branched-chain amino acids in haemodialysis patients with metabolic acidosis. Nephrol Dial Transplant 12:2397–2401PubMedCrossRefGoogle Scholar
  46. Löfberg E, Wernerman J, Anderstam B et al (1997) Correction of acidosis in dialysis patients increases branched-chain and total essential amino acid levels in muscle. Clin Nephrol 48:230–237PubMedGoogle Scholar
  47. Löfberg E, Gutierrez A, Anderstam B et al (2006) Effect of bicarbonate on muscle protein in patients receiving hemodialysis. Am J Kidney Dis 48:419–429PubMedCrossRefGoogle Scholar
  48. Louard RJ, Fryburg DA, Gelfand RA et al (1992) Insulin sensitivity of protein and glucose metabolism in human forearm skeletal muscle. J Clin Invest 90:2348–2354PubMedCrossRefGoogle Scholar
  49. Lu G, Sun H, She P et al (2009) Protein phosphatase 2Cm is a critical regulator of branched-chain amino acid catabolism in mice and cultured cells. J Clin Invest 119:1678–1687PubMedCrossRefGoogle Scholar
  50. Mak RH (1999) Effect of metabolic acidosis on branched-chain amino acids in uremia. Pediatr Nephrol 13:319–322PubMedCrossRefGoogle Scholar
  51. Małgorzewicz S, Debska-Slizień A, Rutkowski B et al (2008) Serum concentration of amino acids versus nutritional status in hemodialysis patients. J Ren Nutr 18:239–247PubMedCrossRefGoogle Scholar
  52. Manders RJ, Koopman R, Sluijsmans WE et al (2006) Co-ingestion of a protein hydrolysate with or without additional leucine effectively reduces postprandial blood glucose excursions in type 2 diabetic men. J Nutr 136:1294–1299PubMedGoogle Scholar
  53. Marchesini G, Bianchi G, Zoli M et al (1983a) Plasma amino acid response to protein ingestion in patients with liver cirrhosis. Gastroenterology 85:283–290PubMedGoogle Scholar
  54. Marchesini G, Forlani G, Zoli M et al (1983b) Effect of euglycemic insulin infusion on plasma levels of branched-chain amino acids in cirrhosis. Hepatology 3:184–187PubMedCrossRefGoogle Scholar
  55. Marchesini G, Bianchi GP, Vilstrup H et al (1987) Plasma clearances of branched-chain amino acids in control subjects and in patients with cirrhosis. J Hepatol 4:108–117PubMedCrossRefGoogle Scholar
  56. Matthews DE, Bier DM, Rennie MJ et al (1981) Regulation of leucine metabolism in man: a stable isotope study. Science 214:1129–1131PubMedCrossRefGoogle Scholar
  57. Matthews DE, Marano MA, Campbell RG (1993) Splanchnic bed utilization of glutamine and glutamic acid in humans. Am J Physiol 264(6 Pt 1):E848–E854PubMedGoogle Scholar
  58. Matthews DE, Harkin R, Battezzati A et al (1999) Splanchnic bed utilization of enteral alpha-ketoisocaproate in humans. Metabolism 48:1555–1563PubMedCrossRefGoogle Scholar
  59. Naylor SL, Shows TB (1980) Branched-chain aminotransferase deficiency in Chinese hamster cells complemented by two independent genes on human chromosomes 12 and 19. Somatic Cell Genet 6:641–652PubMedCrossRefGoogle Scholar
  60. Newgard CB, An J, Bain JR et al (2009) A branched-chain amino acid-related metabolic signature that differentiates obese and lean humans and contributes to insulin resistance. Cell Metab 9:311–326PubMedCrossRefGoogle Scholar
  61. Pacy PJ, Cheng KN, Ford GC et al (1990) Influence of glucagon on protein and leucine metabolism: a study in fasting man with induced insulin resistance. Br J Surg 77:791–794PubMedCrossRefGoogle Scholar
  62. Pietilainen KH, Naukkarinen J, Rissanen A et al (2008) Global transcript profiles of fat in monozygotic twins discordant for BMI: pathways behind acquired obesity. PLoS Med 5:e51PubMedCrossRefGoogle Scholar
  63. Plauth M, Egberts EH, Abele R et al (1990) Characteristic pattern of free amino acids in plasma and skeletal muscle in stable hepatic cirrhosis. Hepatogastroenterology 37:135–139PubMedGoogle Scholar
  64. Pozefsky T, Felig P, Tobin JD et al (1969) Amino acid balance across tissues of the forearm in postabsorptive man. Effects of insulin at two dose levels. J Clin Invest 48:2273–2282PubMedCrossRefGoogle Scholar
  65. Reaich D, Channon SM, Scrimgeour CM et al (1992) Ammonium chloride-induced acidosis increases protein breakdown and amino acid oxidation in humans. Am J Physiol 263(4 Pt 1):E735–E739PubMedGoogle Scholar
  66. Riedel E, Hampl H, Nündel M et al (1992) Essential branched-chain amino acids and alpha-ketoanalogues in haemodialysis patients. Nephrol Dial Transplant 7:117–120PubMedGoogle Scholar
  67. Rudolph HJ, Gerbitz KD, Michal G et al (1981) Enzymic determination of branched-chain amino acids. Clin Chem 27:431–433PubMedGoogle Scholar
  68. Sasaki M, Sato K, Maruhama Y (1988) Rapid changes in urinary serine and branched-chain amino acid excretion among diabetic patients during insulin treatment. Diabetes Res Clin Pract 5:219–224PubMedCrossRefGoogle Scholar
  69. Schauder P, Schäfer G (1987) Oxidation of leucine in human lymphocytes. Scand J Clin Lab Invest 47:447–453PubMedCrossRefGoogle Scholar
  70. Schauder P, Matthaei D, Henning HV et al (1980) Blood levels of branched-chain amino acids and alpha-ketoacids in uremic patients given keto analogues of essential amino acids. Am J Clin Nutr 33:1660–1666PubMedGoogle Scholar
  71. Schauder P, Schröder K, Matthaei D et al (1983) Influence of insulin on blood levels of branched chain keto and amino acids in man. Metabolism 32:323–327PubMedCrossRefGoogle Scholar
  72. Schauder P, Schröder K, Langenbeck U (1984a) Serum branched-chain amino and keto acid response to a protein-rich meal in man. Ann Nutr Metab 28:350–356PubMedCrossRefGoogle Scholar
  73. Schauder P, Schröder K, Herbertz L et al (1984b) Evidence for valine intolerance in patients with cirrhosis. Hepatology 4:667–670PubMedCrossRefGoogle Scholar
  74. Schauder P, Herbertz L, Langenbeck U (1985) Serum branched chain amino and keto acid response to fasting in humans. Metabolism 34:58–61PubMedCrossRefGoogle Scholar
  75. Shaham O, Weil R, Wang TJ et al (2008) Metabolic profiling of the human response to a glucose challenge reveals distinct axes of insulin sensitivity. Mol Syst Biol 214:1–9Google Scholar
  76. She P, Van Horn C, Reid T et al (2007) Obesity-related elevations in plasma leucine are associated with alterations in enzymes involved in branched-chain amino acid metabolism. Am J Physiol Endocrinol Metab 293:E1552–E1563PubMedCrossRefGoogle Scholar
  77. Solini A, Bonora E, Bonadonna R et al (1997) Protein metabolism in human obesity: relationship with glucose and lipid metabolism and with visceral adipose tissue. J Clin Endocrinol Metab 82:2552–2558PubMedCrossRefGoogle Scholar
  78. Stanley CA, Lieu YK, Hsu BY et al (1998) Hyperinsulinism and hyperammonemia in infants with regulatory mutations of the glutamate dehydrogenase gene. N Engl J Med 338:1352–1357PubMedCrossRefGoogle Scholar
  79. Straumann E, Keller U, Küry D et al (1992) Effect of acute acidosis and alkalosis on leucine kinetics in man. Clin Physiol 12:39–51PubMedCrossRefGoogle Scholar
  80. Suryawan A, Hawes JW, Harris RA et al (1998) A molecular model of human branched-chain amino acid metabolism. Am J Clin Nutr 68:72–81PubMedGoogle Scholar
  81. Szabó A, Kenesei E, Körner A et al (1991) Changes in plasma and urinary amino acid levels during diabetic ketoacidosis in children. Diabetes Res Clin Pract 12:91–97PubMedCrossRefGoogle Scholar
  82. Tai ES, Tan ML, Stevens RD et al (2010) Insulin resistance is associated with a metabolic profile of altered protein metabolism in Chinese and Asian-Indian men. Diabetologia 53:757–767PubMedCrossRefGoogle Scholar
  83. Tessari P, Nosadini R, Trevisan R et al (1986) Defective suppression by insulin of leucine-carbon appearance and oxidation in type 1, insulin-dependent diabetes mellitus. Evidence for insulin resistance involving glucose and amino acid metabolism. J Clin Invest 77:1797–1804PubMedCrossRefGoogle Scholar
  84. Tessari P, Garibotto G, Inchiostro S et al. (1996) Kidney, splanchnic, and leg protein turnover in humans. Insight from leucine and phenylalanine kinetics. J Clin Invest 15(98):1481–1492Google Scholar
  85. Tizianello A, De Ferrari G, Gurreri G et al (1977) Effects of metabolic alkalosis, metabolic acidosis and uraemia on whole-body intracellular pH in man. Clin Sci Mol Med 52:125–135PubMedGoogle Scholar
  86. Tizianello A, De Ferrari G, Garibotto G et al (1980) Renal metabolism of amino acids and ammonia in subjects with normal renal function and in patients with chronic renal insufficiency. J Clin Invest 65:1162–1173PubMedCrossRefGoogle Scholar
  87. Tizianello A, Deferrari G, Garibotto G et al (1982) Renal ammoniagenesis in an early stage of metabolic acidosis in man. J Clin Invest 69:240–250PubMedCrossRefGoogle Scholar
  88. Tizianello A, Deferrari G, Garibotto G et al (1983) Branched-chain amino acid metabolism in chronic renal failure. Kidney Int Suppl 16:S17–S22PubMedGoogle Scholar
  89. Trevisan R, Nosadini R, Avogaro A et al (1986) Type I diabetes is characterized by insulin resistance not only with regard to glucose, but also to lipid and amino acid metabolism. J Clin Endocrinol Metab 62:1155–1162PubMedCrossRefGoogle Scholar
  90. Vannini P, Marchesini G, Forlani G et al (1982) Branched-chain amino acids and alanine as indices of the metabolic control in type 1 (insulin-dependent) and type 2 (non-insulin-dependent) diabetic patients. Diabetologia 22:217–219PubMedCrossRefGoogle Scholar
  91. Wahren J, Felig P, Cerasi E et al (1972) Splanchnic and peripheral glucose and amino acid metabolism in diabetes mellitus. J Clin Invest 51:1870–1878PubMedCrossRefGoogle Scholar
  92. Wahren J, Felig P, Hagenfeldt L (1976) Effect of protein ingestion on splanchnic and leg metabolism in normal man and in patients with diabetes mellitus. J Clin Invest 57:987–999PubMedCrossRefGoogle Scholar
  93. Walrand S, Short KR, Bigelow ML et al (2008) Functional impact of high protein intake on healthy elderly people. Am J Physiol Endocrinol Metab 295:E921–E928PubMedCrossRefGoogle Scholar
  94. Walser M, Jarskog FL, Hill SB (1989) Branched-chain-ketoacid metabolism in patients with chronic renal failure. Am J Clin Nutr 50:807–813PubMedGoogle Scholar
  95. Wang TJ, Larson MG, Vasan RS et al (2011) Metabolite profiles and the risk of developing diabetes. Nat Med 17:448–453PubMedCrossRefGoogle Scholar
  96. Zimmerman T, Horber F, Rodriguez N et al (1989) Contribution of insulin resistance to catabolic effect of prednisone on leucine metabolism in humans. Diabetes 38:1238–1244PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag (outside the USA) 2011

Authors and Affiliations

  • María M. Adeva
    • 1
    • 2
    Email author
  • Jesús Calviño
    • 3
  • Gema Souto
    • 4
  • Cristóbal Donapetry
    • 1
  1. 1.Hospital Juan Cardona c/ Pardo Bazán s/nFerrolSpain
  2. 2.OleirosSpain
  3. 3.Hospital Lucus AugustiLugoSpain
  4. 4.Clinical Center of the National Institutes of HealthBethesdaUSA

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