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Frontiers of Medicine

Front Med    2013, Vol. 7 Issue (1) : 53-59
Insulin resistance and the metabolism of branched-chain amino acids
Jingyi Lu1, Guoxiang Xie2,3, Weiping Jia1, Wei Jia2,3()
1. Shanghai Diabetes Institute; Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital; Shanghai Key Laboratory of Diabetes Mellitus; Shanghai Clinical Center for Diabetes, Shanghai 200233, China; 2. Center for Translational Medicine, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai 200233, China; 3. Center for Translational Biomedical Research, University of North Carolina at Greensboro, North Carolina Research Campus, Kannapolis, NC 28081, USA
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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     
Corresponding Author(s): Jia Wei,   
Issue Date: 05 March 2013
 Cite this article:   
Jingyi Lu,Guoxiang Xie,Weiping Jia, et al. Insulin resistance and the metabolism of branched-chain amino acids[J]. Front Med, 2013, 7(1): 53-59.
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Fig.1  A schematic view of the contributions of BCAAs to development of insulin resistance. IR, insulin receptor.
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
doi: 10.1210/er.23.2.201 pmid:11943743
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
doi: 10.1161/01.ATV.0000111245.75752.C6 pmid:14766739
3 Rader DJ. Effect of insulin resistance, dyslipidemia, and intra-abdominal adiposity on the development of cardiovascular disease and diabetes mellitus. Am J Med 2007; 120(3 Suppl 1): S12-S18
doi: 10.1016/j.amjmed.2007.01.003 pmid:17320517
4 World Health Organization. Obesity and overweight: Fact sheet N°311. 2012
5 American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care 2009; 32(Suppl 1): S62-S67
doi: 10.2337/dc09-S062 pmid:19118289
6 Layman DK. The role of leucine in weight loss diets and glucose homeostasis. J Nutr 2003; 133(1): 261S-267S
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
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
doi: 10.1152/ajpendo.00609.2006 pmid:17299083
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
doi: 10.1152/ajpgi.00510.2003 pmid:15591158
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
doi: 10.1126/science.1124147 pmid:16690869
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
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
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
doi: 10.1016/0026-0495(88)90089-3 pmid:3290625
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
doi: 10.1056/NEJM196910092811503 pmid:5809519
15 Felig P, Marliss E, Cahill GF Jr. Are plasma amino acid levels elevated in obesity? N Engl J Med 1970; 282(3): 166
doi: 10.1056/NEJM197001152820315 pmid:5409545
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
doi: 10.1038/sj.ijo.0801195 pmid:10849575
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 Metab 2009; 9(4): 311-326
doi: 10.1016/j.cmet.2009.02.002 pmid:19356713
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
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 Care 2001; 4(5): 419-423
doi: 10.1097/00075197-200109000-00013 pmid:11568504
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
doi: 10.1152/ajpendo.00276.2003 pmid:12965870
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
doi: 10.1021/pr2009725 pmid:22115128
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
doi: 10.1016/S0065-2571(96)00009-X pmid:9381974
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
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
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
doi: 10.2337/dc08-2075 pmid:19502541
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
doi: 10.1038/msb.2008.50 pmid:18682704
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
doi: 10.1007/s00125-009-1637-8 pmid:20076942
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
doi: 10.1038/nm.2307 pmid:21423183
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 pmid:10.2337/db12-049523043162" target="blank">
doi: 10.2337/db12-049523043162
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, D?ring 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
doi: 10.1038/msb.2012.43 pmid:23010998
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
doi: 10.1111/j.2047-6310.2012.00087.x pmid:22961720
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. Diabetologia 2012; 55(2): 321-330
doi: 10.1007/s00125-011-2356-5 pmid:22065088
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
doi: 10.1126/scitranslmed.3002043 pmid:21525399
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
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
doi: 10.1016/S0955-2863(98)00098-9 pmid:15539297
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
doi: 10.1210/en.2006-0251 pmid:16777975
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
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
doi: 10.1016/j.cmet.2007.08.003 pmid:17767905
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
doi: 10.1152/ajpendo.00134.2007 pmid:17925455
40 Pietil?inen KH, Naukkarinen J, Rissanen A, Saharinen J, Ellonen P, Ker?nen H, Suomalainen A, G?tz A, Suortti T, Yki-J?rvinen 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
doi: 10.1371/journal.pmed.0050051 pmid:18336063
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
doi: 10.1074/jbc.M109.075184 pmid:20093359
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
doi: 10.1152/ajpendo.00219.2010 pmid:20959535
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
doi: 10.1073/pnas.0903032106 pmid:19841271
44 Lefort N, Glancy B, Bowen B, Willis WT, Bailowitz Z, De Filippis EA, Brophy C, Meyer C, H?jlund 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
doi: 10.2337/db10-0174 pmid:20682693
45 Hay N, Sonenberg N. Upstream and downstream of mTOR. Genes Dev 2004; 18(16): 1926-1945
doi: 10.1101/gad.1212704 pmid:15314020
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
doi: 10.1016/S0092-8674(02)00833-4 pmid:12150926
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 Endocrinol 2000; 14(6): 783-794
doi: 10.1210/me.14.6.783 pmid:10847581
48 O’Connor JC, Freund GG. Vanadate and rapamycin synergistically enhance insulin-stimulated glucose uptake. Metabolism 2003; 52(6): 666-674
doi: 10.1016/S0026-0495(03)00026-X pmid:12800089
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
doi: 10.2337/diabetes.50.1.24 pmid:11147790
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
doi: 10.1038/352073a0 pmid:1648180
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
doi: 10.1128/MCB.26.1.63-76.2006 pmid:16354680
52 Tremblay F, Krebs M, Dombrowski L, Brehm A, Bernroider E, Roth E, Nowotny P, Waldh?usl 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
doi: 10.2337/diabetes.54.9.2674 pmid:16123357
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
doi: 10.2337/db10-1246 pmid:21282364
54 Bruhat A, Jousse C, Fafournoux P. Amino acid limitation regulates gene expression. Proc Nutr Soc 1999; 58(3): 625-632
doi: 10.1017/S0029665199000828 pmid:10604196
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
doi: 10.1146/annurev.nutr.24.012003.132145 pmid:16011459
56 Guo F, Cavener DR. The GCN2 eIF2alpha kinase regulates fatty-acid homeostasis in the liver during deprivation of an essential amino acid. Cell Metab 2007; 5(2): 103-114
doi: 10.1016/j.cmet.2007.01.001 pmid:17276353
57 Macotela Y, Emanuelli B, B?ng 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
doi: 10.1371/journal.pone.0021187 pmid:21731668
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
doi: 10.2337/db07-0123 pmid:17360978
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
doi: 10.3945/jn.108.100081 pmid:19244380
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