Are BCAAs Mere Biomarkers of Diabetes?
DOI:
https://doi.org/10.17140/DROJ-3-e009Abstract
Branched-chain amino acids (BCAAs; ie. leucine, isoleucine, and valine) are essential amino acids we need to ingest through our diet.While circulating BCAA levels were first found to be elevated in obese individuals back in 1969 by Felig and colleagues,1 the potential role of BCAAs in obesity and diabetes development has been re-highlighted in the last decade. Using advanced metabolomic platforms, many independent investigators were able to reproduce the earlier finding and further demonstrate that not only plasma BCAAs, but also their partially oxidized intermediates such as α-keto acids and short-chain (C3-C5) acylcarnitines are increased in obese or insulin resistant/diabetic individuals, including Caucasians and Asians.2-9 Moreover, plasma BCAAs are found to be the earliest and the most predictive marker for future risk of diabetes,10 and elevated plasma leucine levels precede the development of fatty liver,11 suggesting that circulating leucine is a predictive marker of hepatic steatosis. Interestingly, plasma BCAAs and their derived short-chain acylcarnitines are effectively lowered by bariatric surgery in obese and/or diabetic individuals.5,8,12,13 Whether this normalized BCAA metabolism after RYGB surgery in morbidly obese patients contributes to improved insulin sensitivity and glycemic control or is just a secondary effect of the surgery needs to be examined further. Nonetheless, collectively these studies implicate a role of plasma BCAAs and their metabolites in the pathogenesis of insulin resistance and diabetes.
References
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
Adams SH, Hoppel CL, Lok KH, et al. Plasma acylcarnitine profiles suggest incomplete long-chain fatty acid beta-oxidation and altered tricarboxylic acid cycle activity in type 2 diabetic African-American women. J Nutr. 2009; 139(6): 1073-1081. doi: 10.3945/ jn.108.103754
Kim JY, Park JY, Kim OY, et al. Metabolic profiling of plasma in overweight/obese and lean men using ultra performance liq-uid chromatography and Q-TOF mass spectrometry (UPLC-Q-TOF MS). J Proteome Res. 2010; 9(9): 4368-4375. doi: 10.1021/ pr100101p
Koves TR, Ussher JR, Noland RC, et al. Mitochondrial overload and incomplete fatty acid oxidation contribute to skeletal muscle insulin resistance. Cell Metab. 2008; 7(1): 45-56. doi: 10.1016/j.cmet.2007.10.013
Laferrere B, Reilly D, Arias S, et al. Differential metabolic impact of gastric bypass surgery versus dietary intervention in obese diabetic subjects despite identical weight loss. Sci Transl Med. 2011; 3(80): 80-82. doi: 10.1126/scitranslmed.3002043
Mihalik SJ, Goodpaster BH, Kelley DE, et al. Increased levels of plasma acylcarnitines in obesity and type 2 diabetes and identi-fication of a marker of glucolipotoxicity. Obesity (Silver Spring). 2010; 18(9): 1695-1700. doi: 10.1038/oby.2009.510
Newgard CB, An J, Bain JR, 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): 311-326. doi: 10.1016/j.cmet.2009.02.002
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
Tai ES, Tan ML, Stevens RD, et al. Insulin resistance is associated with a metabolic profile of altered protein metabolism in Chi-nese and Asian-Indian men. Diabetologia. 2010; 53(4): 757-767. doi: 10.1007/s00125-009-1637-8
Wang TJ, Larson MG, Vasan RS, et al. Metabolite profiles and the risk of developing diabetes. Nat Med. 2011; 17(4): 448-453. doi: 10.1038/nm.2307
Kaikkonen JE, Wurtz P, Suomela E, et al. Metabolic profiling of fatty liver in young and middle-aged adults: Cross-sectional and prospective analyses of the Young Finns Study. Hepatology. 2016. doi: 10.1002/hep.28899
Mutch DM, Fuhrmann JC, Rein D, et al. Metabolite profiling identifies candidate markers reflecting the clinical adaptations as-sociated with Roux-en-Y gastric bypass surgery. PLoS One. 2009; 4(11): e7905. doi: 10.1371/journal.pone.0007905
Magkos F, Bradley D, Schweitzer GG, et al. Effect of Roux-en-Y gastric bypass and laparoscopic adjustable gastric banding on branched-chain amino acid metabolism. Diabetes. 2013; 62(8): 2757-2761. doi: 10.2337/db13-0185
Tsien C, Davuluri G, Singh D, et al. Metabolic and molecular responses to leucine-enriched branched chain amino acid supple-mentation in the skeletal muscle of alcoholic cirrhosis. Hepatology. 2015; 61(6): 2018-2029. doi: 10.1002/hep.27717
Matsuoka S, Tamura A, Nakagawara H, Moriyama M. Improvement in the nutritional status and clinical conditions of patients with liver failure using a liver diet combined with a branched chain amino acids-enriched elemental diet. Hepatogastroenterology. 2014; 61(133): 1308-1312. Web site. http://europepmc.org/abstract/med/25513087. Accessed January 1, 2017.
Chin SE, Shepherd RW, Thomas BJ, et al. Nutritional support in children with end-stage liver disease: A randomized crossover trial of a branched-chain amino acid supplement. Am J Clin Nutr. 1992; 56(1): 158-163. Web site. http://ajcn.nutrition.org/con-tent/56/1/158.short. Accessed January 1, 2017.
Habu D, Nishiguchi S, Nakatani S, et al. Effect of oral supplementation with branched-chain amino acid granules on serum albu-min level in the early stage of cirrhosis: A randomized pilot trial. Hepatol Res. 2003; 25(3): 312-318. doi: 10.1007/4-431-27172-4_9
Tietze IN, Pedersen EB. Effect of fish protein supplementation on aminoacid profile and nutritional status in haemodialysis patients. Nephrol Dial Transplant. 1991; 6(12): 948-954. doi: 10.1093/ndt/6.12.948
Ishihara T, Iwasa M, Tanaka H, et al. Effect of branched-chain amino acids in patients receiving intervention for hepatocellular carcinoma. World J Gastroenterol. 2014; 20(10): 2673-2680. doi: 10.3748/wjg.v20.i10.2673
Kakazu E, Kondo Y, Kogure T, et al. Supplementation of branched-chain amino acids maintains the serum albumin level in the course of hepatocellular carcinoma recurrence. Tohoku J Exp Med. 2013; 230(4): 191-196. doi: 10.1620/tjem.230.191
Choudry HA, Pan M, Karinch AM, Souba WW. Branched-chain amino acid-enriched nutritional support in surgical and cancer patients. J Nutr Jan. 2006; 136(1 Suppl): 314S-318S. Web site. http://jn.nutrition.org/content/136/1/314S.long. Accessed January 1, 2017.
Togo S, Tanaka K, Morioka D, et al. Usefulness of granular BCAAs after hepatectomy for liver cancer complicated with liver cirrhosis. Nutrition. 2005; 21(4): 480-486. doi: 10.1016/j.nut.2004.07.017
Bower RH, Muggia-Sullam M, Vallgren S, et al. Branched chain amino acid-enriched solutions in the septic patient. A ran-domized, prospective trial. Ann Surg. 1986; 203(1): 13-20. Web site. http://journals.lww.com/annalsofsurgery/Citation/1986/01000/ Branched_Chain_Amino_Acid_Enriched_Solutions_in.3.aspx. Accessed January 1, 2017.
Jimenez Jimenez FJ, Ortiz Leyba C, Morales Menedez S, Barros Perez M, Munoz Garcia J. Prospective study on the efficacy of branched-chain amino acids in septic patients. JPEN J Parenter Enteral Nutr. 1991; 15(3): 252-261. doi: 10.1177/0148607191015003252
Garcia-de-Lorenzo A, Ortiz-Leyba C, Planas M, et al. Parenteral administration of different amounts of branch-chain amino acids in septic patients: Clinical and metabolic aspects. Crit Care Med. 1997; 25(3): 418-424. Web site. http://journals.lww.com/ ccmjournal/Abstract/1997/03000/Parenteral_administration_of_different_amounts_of.8.aspx. Accessed January 1, 2017.
Jeganathan S, Abdullahi A, Zargar S, Maeda N, Riddell MC, Adegoke OA. Amino acid-induced impairment of insulin sensitivity in healthy and obese rats is reversible. Physiol Rep. 2014; 2(7): e12067. doi: 10.14814/phy2.12067
Tremblay F, Krebs M, Dombrowski L, et al. Overactivation of S6 kinase 1 as a cause of human insulin resistance during in-creased amino acid availability. Diabetes. 2005; 54(9): 2674-2684. doi: 10.2337/diabetes.54.9.2674
Tremblay F, Marette A. Amino acid and insulin signaling via the mTOR/p70 S6 kinase pathway. A negative feedback mecha-nism leading to insulin resistance in skeletal muscle cells. J Biol Chem. 2001; 276(41): 38052-38060. Web site. http://www.jbc.org/ content/276/41/38052.short. Accessed January 1, 2017.
Funchal C, Latini A, Jacques-Silva MC, et al. Morphological alterations and induction of oxidative stress in glial cells caused by the branched-chain alpha-keto acids accumulating in maple syrup urine disease. Neurochem Int. 2006; 49(7): 640-650. doi: 10.1016/j.neuint.2006.05.007
Bridi R, Braun CA, Zorzi GK, et al. alpha-keto acids accumulating in maple syrup urine disease stimulate lipid peroxidation and reduce antioxidant defences in cerebral cortex from young rats. Metab Brain Dis. 2005; 20(2): 155-167. doi: 10.1007/s11011- 005-4152-8
Lu G, Sun H, She 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): 1678-1687. doi: 10.1172/JCI38151DS1
Oyarzabal A, Martinez-Pardo M, Merinero B, et al. A novel regulatory defect in the branched-chain alpha-keto acid dehydro-genase complex due to a mutation in the PPM1K gene causes a mild variant phenotype of maple syrup urine disease. Hum Mutat. 2013; 34(2): 355-362. doi: 10.1002/humu.22242
Amaral AU, Leipnitz G, Fernandes CG, Seminotti B, Schuck PF, Wajner M. Alpha-ketoisocaproic acid and leucine provoke mitochondrial bioenergetic dysfunction in rat brain. Brain Res. 2010; 1324: 75-84. doi: 10.1016/j.brainres.2010.02.018
Lu G, Ren S, Korge P, et al. A novel mitochondrial matrix serine/threonine protein phosphatase regulates the mitochondria permeability transition pore and is essential for cellular survival and development. Genes Dev. 2007; 21(7): 784-796. doi: 10.1101/ gad.1499107
Jouvet P, Rustin P, Taylor DL, et al. Branched chain amino acids induce apoptosis in neural cells without mitochondrial mem-brane depolarization or cytochrome c release: Implications for neurological impairment associated with maple syrup urine disease. Mol Biol Cell. 2000; 11(5): 1919-1932. doi: 10.1091/mbc.11.5.1919
Jouvet P, Kozma M, Mehmet H. Primary human fibroblasts from a maple syrup urine disease patient undergo apoptosis fol-lowing exposure to physiological concentrations of branched chain amino acids. Ann N Y Acad Sci. 2000; 926: 116-121. doi: 10.1111/j.1749-6632.2000.tb05604.x
Balage M, Dupont J, Mothe-Satney I, Tesseraud S, Mosoni L, Dardevet D. Leucine supplementation in rats induced a delay in muscle IR/PI3K signaling pathway associated with overall impaired glucose tolerance. J Nutr Biochem. 2011; 22(3): 219-226. doi: 10.1016/j.jnutbio.2010.02.001
Nicastro H, Zanchi NE, da Luz CR, et al. Effects of leucine supplementation and resistance exercise on dexamethasone-induced muscle atrophy and insulin resistance in rats. Nutrition. 2012; 28(4): 465-471. doi: 10.1016/j.nut.2011.08.008
Zanchi NE, Guimaraes-Ferreira L, de Siqueira-Filho MA, et al. Dose and latency effects of leucine supplementation in modulat-ing glucose homeostasis: Opposite effects in healthy and glucocorticoid-induced insulin-resistance states. Nutrients. 2012; 4(12): 1851-1867. doi: 10.3390/nu4121851
Krebs M, Krssak M, Bernroider E, et al. Mechanism of amino acid-induced skeletal muscle insulin resistance in humans. Dia-betes. 2002; 51(3): 599-605. doi: 10.2337/diabetes.51.3.599
Saha AK, Xu XJ, Lawson E, et al. Downregulation of AMPK accompanies leucine- and glucose-induced increases in protein synthesis and insulin resistance in rat skeletal muscle. Diabetes. 2010; 59(10): 2426-2434. doi: 10.2337/db09-1870
Baum JI, Washington TA, Shouse SA, et al. Leucine supplementation at the onset of high-fat feeding does not prevent weight gain or improve glycemic regulation in male Sprague-Dawley rats. J Physiol Biochem. 2016; 72(4): 781-789. doi: 10.1007/s13105- 016-0516-2
Moghei M, Tavajohi-Fini P, Beatty B, Adegoke OA. Ketoisocaproic acid, a metabolite of leucine, suppresses insulin-stimulated glucose transport in skeletal muscle cells in a BCAT2-dependent manner. Am J Physiol Cell Physiol. 2016; 311(3): C518-C527. doi: 10.1152/ajpcell.00062.2016
Jang C, Oh SF, Wada S, et al. A branched-chain amino acid metabolite drives vascular fatty acid transport and causes insulin resistance. Nat Med. 2016; 22(4): 421-426. doi: 10.1038/nm.4057
Lerin C, Goldfine AB, Boes T, et al. Defects in muscle branched-chain amino acid oxidation contribute to impaired lipid metabo-lism. Mol Metab. 2016; 5(10): 926-936. doi: 10.1016/j.molmet.2016.08.001
Du Y, Meng Q, Zhang Q, Guo F. Isoleucine or valine deprivation stimulates fat loss via increasing energy expenditure and regu-lating lipid metabolism in WAT. Amino Acids. 2012; 43(2): 725-734. doi: 10.1007/s00726-011-1123-8
Cheng Y, Meng Q, Wang C, et al. Leucine deprivation decreases fat mass by stimulation of lipolysis in white adipose tissue and upregulation of uncoupling protein 1 (UCP1) in brown adipose tissue. Diabetes. 2010; 59(1): 17-25. doi: 10.2337/db09-0929
White PJ, Lapworth AL, An J, et al. Branched-chain amino acid restriction in Zucker-fatty rats improves muscle insulin sen-sitivity by enhancing efficiency of fatty acid oxidation and acyl-glycine export. Mol Metab. 2016; 5(7): 538-551. doi: 10.1016/j. molmet.2016.04.006
Tessari P, Cecchet D, Cosma A, et al. Insulin resistance of amino acid and protein metabolism in type 2 diabetes. Clin Nutr. 2011; 30(3): 267-272. doi: 10.1016/j.clnu.2011.02.009
Pietilainen KH, Naukkarinen J, Rissanen A, et al. 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
Shin AC, Fasshauer M, Filatova N, et al. Brain insulin lowers circulating BCAA levels by inducing hepatic BCAA catabolism. Cell Metab. 2014; 20(5): 898-909. doi: 10.1016/j.cmet.2014.09.003
Lackey DE, Lynch CJ, Olson KC, et al. Regulation of adipose branched-chain amino acid catabolism enzyme expression and cross-adipose amino acid flux in human obesity. Am J Physiol Endocrinol Metab. 2013; 304(11): E1175-E1187. doi: 10.1152/ ajpendo.00630.2012
Schauder P, Schroder K, Matthaei D, Henning HV, Langenbeck U. Influence of insulin on blood levels of branched chain keto and amino acids in man. Metabolism. 1983; 32(4): 323-327. doi: 10.1016/0026-0495(83)90038-0
Tessari P, Nosadini R, Trevisan R, et al. 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. 1986; 77(6): 1797-1804. Web site. http://www.jci.org/articles/view/112504. Accessed January 1, 2017.
Caballero B, Wurtman RJ. Differential effects of insulin resistance on leucine and glucose kinetics in obesity. Metabolism. 1991; 40(1): 51-58. doi: 10.1016/0026-0495(91)90192-Y
Forlani G, Vannini P, Marchesini G, Zoli M, Ciavarella A, Pisi E. Insulin-dependent metabolism of branched-chain amino acids in obesity. Metabolism. 1984; 33(2): 147-150. doi: 10.1016/0026-0495(84)90127-6
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