Insulin resistance and the metabolism of branched-chain amino acids

Jingyi Lu, Guoxiang Xie, Weiping Jia, Wei Jia

PDF(196 KB)
PDF(196 KB)
Front. Med. ›› 2013, Vol. 7 ›› Issue (1) : 53-59. DOI: 10.1007/s11684-013-0255-5
REVIEW
REVIEW

Insulin resistance and the metabolism of branched-chain amino acids

Author information +
History +

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.

Keywords

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

Cite this article

Download citation ▾
Jingyi Lu, Guoxiang Xie, Weiping Jia, Wei Jia. Insulin resistance and the metabolism of branched-chain amino acids. Front Med, 2013, 7(1): 53‒59 https://doi.org/10.1007/s11684-013-0255-5

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 Rev2002; 23(2): 201-229
CrossRef Pubmed 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 Biol2004; 24(2): e13-e18
CrossRef Pubmed Google scholar
[3]
Rader DJ. Effect of insulin resistance, dyslipidemia, and intra-abdominal adiposity on the development of cardiovascular disease and diabetes mellitus. Am J Med2007; 120(3 Suppl 1): S12-S18
CrossRef Pubmed Google scholar
[4]
World Health Organization. Obesity and overweight: Fact sheet N°311. 2012
[5]
American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care2009; 32(Suppl 1): S62-S67
CrossRef Pubmed Google scholar
[6]
Layman DK. The role of leucine in weight loss diets and glucose homeostasis. J Nutr2003; 133(1): 261S-267S
Pubmed
[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 Nutr2005; 135(9): 2103-2108
Pubmed
[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 Metab2007; 292(6): E1683-E1693
CrossRef Pubmed 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 Physiol2005; 288(6): G1292-G1300
CrossRef Pubmed Google scholar
[10]
Cota D, Proulx K, Smith KA, Kozma SC, Thomas G, Woods SC, Seeley RJ. Hypothalamic mTOR signaling regulates food intake. Science2006; 312(5775): 927-930
CrossRef Pubmed 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 Nutr2006; 136(7): 1855-1861
Pubmed
[12]
Layman DK, Walker DA. Potential importance of leucine in treatment of obesity and the metabolic syndrome. J Nutr2006; 136(1 Suppl): 319S-323S
Pubmed
[13]
Caballero B, Finer N, Wurtman RJ. Plasma amino acids and insulin levels in obesity: response to carbohydrate intake and tryptophan supplements. Metabolism1988; 37(7): 672-676
CrossRef Pubmed Google scholar
[14]
Felig P, Marliss E, Cahill GF Jr. Plasma amino acid levels and insulin secretion in obesity. N Engl J Med1969; 281(15): 811-816
CrossRef Pubmed Google scholar
[15]
Felig P, Marliss E, Cahill GF Jr. Are plasma amino acid levels elevated in obesity? N Engl J Med1970; 282(3): 166
CrossRef Pubmed 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 Disord2000; 24(5): 552-558
CrossRef Pubmed 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 branched-chain amino acid-related metabolic signature that differentiates obese and lean humans and contributes to insulin resistance. Cell Metab2009; 9(4): 311-326
CrossRef Pubmed 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 Nutr2006; 136(1 Suppl): 250S-253S
Pubmed
[19]
Shimomura Y, Obayashi M, Murakami T, Harris RA. Regulation of branched-chain amino acid catabolism: nutritional and hormonal regulation of activity and expression of the branched-chain alpha-keto acid dehydrogenase kinase. Curr Opin Clin Nutr Metab Care2001; 4(5): 419-423
CrossRef Pubmed 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 Metab2004; 286(1): E64-E76
CrossRef Pubmed 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 Res2012; 11(2): 1302-1316
CrossRef Pubmed 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 Regul1997; 37: 271-293
CrossRef Pubmed 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 Chem1992; 267(19): 13127-13130
Pubmed
[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 Chem1987; 262(11): 5129-5132
Pubmed
[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 Care2009; 32(9): 1678-1683
CrossRef Pubmed 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 Biol2008; 4: 214
CrossRef Pubmed 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. Diabetologia2010; 53(4): 757-767
CrossRef Pubmed 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 Med2011; 17(4): 448-453
CrossRef Pubmed 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]
CrossRef Pubmed Google scholar
[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 Biol2012; 8: 615
CrossRef Pubmed 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 Obes2013; 8(1): 52-61
CrossRef Pubmed 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. Branched-chain amino acid levels are associated with improvement in insulin resistance with weight loss. Diabetologia2012; 55(2): 321-330
CrossRef Pubmed 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 Med2011; 3(80):80re2
CrossRef Pubmed 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 Physiol1996; 270(2 Pt 1): E273-E281
Pubmed
[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 Biochem1999; 10(4): 244-248
CrossRef Pubmed 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. Endocrinology2006; 147(9): 4160-4168
CrossRef Pubmed 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 Nutr1998; 68(1): 72-81
Pubmed
[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 Metab2007; 6(3): 181-194
CrossRef Pubmed 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 Metab2007; 293(6): E1552-E1563
CrossRef Pubmed 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 Med2008; 5(3): e51
CrossRef Pubmed 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 Chem2010; 285(15): 11348-11356
CrossRef Pubmed 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 Metab2011; 300(1): E164-E174
CrossRef Pubmed 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 USA2009; 106(44): 18745-18750
CrossRef Pubmed 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. Diabetes2010; 59(10): 2444-2452
CrossRef Pubmed Google scholar
[45]
Hay N, Sonenberg N. Upstream and downstream of mTOR. Genes Dev2004; 18(16): 1926-1945
CrossRef Pubmed 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. Cell2002; 110(2): 177-189
CrossRef Pubmed Google scholar
[47]
Haruta T, Uno T, Kawahara J, Takano A, Egawa K, Sharma PM, Olefsky JM, Kobayashi M. A rapamycin-sensitive pathway down-regulates insulin signaling via phosphorylation and proteasomal degradation of insulin receptor substrate-1. Mol Endocrinol2000; 14(6): 783-794
CrossRef Pubmed Google scholar
[48]
O’Connor JC, Freund GG. Vanadate and rapamycin synergistically enhance insulin-stimulated glucose uptake. Metabolism2003; 52(6): 666-674
CrossRef Pubmed Google scholar
[49]
Pederson TM, Kramer DL, Rondinone CM. Serine/threonine phosphorylation of IRS-1 triggers its degradation: possible regulation by tyrosine phosphorylation. Diabetes2001; 50(1): 24-31
CrossRef Pubmed 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. Nature1991; 352(6330): 73-77
CrossRef Pubmed 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 Biol2006; 26(1): 63-76
CrossRef Pubmed 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. Diabetes2005; 54(9): 2674-2684
CrossRef Pubmed 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. Diabetes2011; 60(3): 746-756
CrossRef Pubmed Google scholar
[54]
Bruhat A, Jousse C, Fafournoux P. Amino acid limitation regulates gene expression. Proc Nutr Soc1999; 58(3): 625-632
CrossRef Pubmed 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 Nutr2005; 25(1): 59-85
CrossRef Pubmed Google scholar
[56]
Guo F, Cavener DR. The GCN2 eIF2alpha kinase regulates fatty-acid homeostasis in the liver during deprivation of an essential amino acid. Cell Metab2007; 5(2): 103-114
CrossRef Pubmed 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 ONE2011; 6(6): e21187
CrossRef Pubmed 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. Diabetes2007; 56(6): 1647-1654
CrossRef Pubmed 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 Nutr2009; 139(4): 715-719
CrossRef Pubmed Google scholar

Acknowledgements

This work was supported by grants from the National Basic Research Program of China (973 Program, 2011CB504001) and the National Natural Science Foundation of China (Grant Nos. 81100590 and 81170760).

RIGHTS & PERMISSIONS

2014 Higher Education Press and Springer-Verlag Berlin Heidelberg
AI Summary AI Mindmap
PDF(196 KB)

Accesses

Citations

Detail

Sections
Recommended

/