Diabetes Research

Open journal

ISSN 2379-6375

Are BCAAs Mere Biomarkers of Diabetes?

Andrew C. Shin*

Andrew C. Shin, PhD

Assistant Professor Department of Nutritional Sciences College of Human Sciences Texas Tech University Lubbock, TX, USA E-mail: andrew.shin@ttu.edu

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.2,3,4,5,6,7,8,9 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.

The unresolved question in the field today is whether or not they are mere biomarkers or they are one of the potential culprits for derangement of glucose metabolism and development of obesity and insulin resistance/diabetes. While a number of studies demonstrate that either amino acid mixture or BCAA supplementation have beneficial effects on protein turnover and muscle wasting in patients with cirrhosis, kidney failure, cancer, or sepsis,14,15,16,17,18,19,20,21,22,23,24,25 mounting evidence suggests that amino acids/BCAAs or their metabolized keto acids lead to hyperactivation of mTOR signaling,7,26,27,28 induction of oxidative stress,29,30,31,32 mitochondrial dysfunction,33,34 apoptosis,35,36 and more importantly, insulin resistance and/or impaired glucose metabolism. 7,26,27,28,37,38,39,40,41,42,43,44 Consistent with these findings, recent studies demonstrate that a BCAA metabolite elevated in diabetic individuals can drive vascular fatty acid transport in muscle and induce insulin resistance in mice44 and a defective muscle BCAA metabolism induces impaired lipid metabolism and insulin resistance.45 On the other hand, deprivation of a single or all three BCAAs improves insulin sensitivity and glycemic control in either chow- or High-Fat Diet (HFD)-fed, or genetically diabetic rodents.46,47,48 These findings strongly indicate not only a correlative, but also a causative role of circulating BCAAs and their oxidized intermediates in the development of insulin resistance and diabetes. As such, it is important to advance our understanding of BCAA regulatory mechanisms that would allow us to explain the reasons for high circulating levels of BCAAs found in obese and diabetic individuals.

The rise of plasma BCAAs in the obese and/or diabetic individuals may be simply because they take in more BCAAs due to their increased food consumption in general. But BCAAs levels are still higher in these individuals even after overnight fasting, or even when they match the amount of protein intake with lean individuals.9,10 Alternatively, the higher plasma BCAAs may be attributed to an increased release of endogenous BCAAs through protein breakdown or decreased BCAAs utilization in tissues due to decreased protein synthesis in these individuals, but both whole-body proteolysis and protein synthesis are not different between diabetic and normal individuals, as they have been extensively reviewed by Tessari and colleagues.49 Rather, the increased circulating BCAAs and their intermediates may be because of decreased or impaired BCAAs degradation in tissues like liver, muscle, and adipose tissue. This concept of impaired BCAAs metabolism in obesity and diabetes is supported by findings demonstrating decreased gene expressions of BCAA-degrading enzymes in subcutaneous and omental fat tissues in obese twins compared to their lean monozygotic co-twins,50 decreased protein or activity of branched-chain α-keto acid dehydrogenase (BCKDH), the rate-limiting enzyme in BCAA degradation pathway, in livers of obese ob/ob mice and diabetic fa/fa rats,8 in HFD fed rats and diet-induced obese men and monkeys,51 as well as in obese Pima Indians.52 The reasons for dysregulated BCAA metabolism in obese and diabetics are unclear. Systemic insulin lowers circulating BCAAs in normal healthy subjects but less so in obese and diabetic individuals, indicating insulin resistance as a major cause for the elevated BCAA in obesity and diabetes.53,54,55,56 We have recently revealed for the first time the role of insulin in the regulation of BCAA metabolism by demonstrating that insulin dose-dependently lowers plasma BCAAs independent of glycemia via induction of hepatic BCAA catabolism.51 We further showed that this control of BCAA metabolism is mediated primarily through insulin action in the brain, and that impaired BCAA metabolism and the resultant higher plasma BCAA levels ensue in a state of central insulin resistance.51

Future studies examining the underlying mechanisms of BCAA-induced impairment of glucose or lipid partitioning, and the role of this novel neuroendocrine control of BCAA metabolism in either glucose or lipid homeostasis would give us new mechanistic insights into development of insulin resistance and diabetes and offer interventional or preventive therapeutic strategies to fight them.

CONFLICTS OF INTEREST

The author declares no conflicts of interest.

1. 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

2. 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

3. Kim JY, Park JY, Kim OY, et al. Metabolic profiling of plasma in overweight/obese and lean men using ultra performance liquid chromatography and Q-TOF mass spectrometry (UPLC-Q-TOF MS). J Proteome Res. 2010; 9(9): 4368-4375. doi: 10.1021/pr100101p

4. 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

5. 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

6. Mihalik SJ, Goodpaster BH, Kelley DE, et al. Increased levels of plasma acylcarnitines in obesity and type 2 diabetes and identification of a marker of glucolipotoxicity. Obesity (Silver Spring). 2010; 18(9): 1695-1700. doi: 10.1038/oby.2009.510

7. 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

8. 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

9. Tai ES, Tan ML, Stevens RD, et al. 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

10. 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

11. 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

12. Mutch DM, Fuhrmann JC, Rein D, et al. Metabolite profiling identifies candidate markers reflecting the clinical adaptations associated with Roux-en-Y gastric bypass surgery. PLoS One. 2009; 4(11): e7905. doi: 10.1371/journal.pone.0007905

13. 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

14. Tsien C, Davuluri G, Singh D, et al. Metabolic and molecular responses to leucine-enriched branched chain amino acid supplementation in the skeletal muscle of alcoholic cirrhosis. Hepatology. 2015; 61(6): 2018-2029. doi: 10.1002/hep.27717

15. 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.

16. 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/content/56/1/158.short. Accessed January 1, 2017.

17. Habu D, Nishiguchi S, Nakatani S, et al. Effect of oral supplementation with branched-chain amino acid granules on serum albumin 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

18. 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

19. 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

20. 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

21. 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.

22. 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

23. Bower RH, Muggia-Sullam M, Vallgren S, et al. Branched chain amino acid-enriched solutions in the septic patient. A randomized, 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.

24. 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

25. 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.

26. 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

27. Tremblay F, Krebs M, Dombrowski L, et al. 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

28. Tremblay F, Marette A. Amino acid and insulin signaling via the mTOR/p70 S6 kinase pathway. A negative feedback mechanism 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.

29. 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

30. 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

31. 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

32. Oyarzabal A, Martinez-Pardo M, Merinero B, et al. A novel regulatory defect in the branched-chain alpha-keto acid dehydrogenase 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

33. 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

34. 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

35. Jouvet P, Rustin P, Taylor DL, et al. Branched chain amino acids induce apoptosis in neural cells without mitochondrial membrane 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

36. Jouvet P, Kozma M, Mehmet H. Primary human fibroblasts from a maple syrup urine disease patient undergo apoptosis following 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

37. 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

38. 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

39. Zanchi NE, Guimaraes-Ferreira L, de Siqueira-Filho MA, et al. Dose and latency effects of leucine supplementation in modulating glucose homeostasis: Opposite effects in healthy and glucocorticoid-induced insulin-resistance states. Nutrients. 2012; 4(12): 1851-1867. doi: 10.3390/nu4121851

40. Krebs M, Krssak M, Bernroider E, et al. Mechanism of amino acid-induced skeletal muscle insulin resistance in humans. Diabetes. 2002; 51(3): 599-605. doi: 10.2337/diabetes.51.3.599

41. 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

42. 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

43. 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

44. 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

45. Lerin C, Goldfine AB, Boes T, et al. Defects in muscle branched-chain amino acid oxidation contribute to impaired lipid metabolism. Mol Metab. 2016; 5(10): 926-936. doi: 10.1016/j.molmet.2016.08.001

46. Du Y, Meng Q, Zhang Q, Guo F. Isoleucine or valine deprivation stimulates fat loss via increasing energy expenditure and regulating lipid metabolism in WAT. Amino Acids. 2012; 43(2): 725-734. doi: 10.1007/s00726-011-1123-8

47. 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

48. White PJ, Lapworth AL, An J, et al. Branched-chain amino acid restriction in Zucker-fatty rats improves muscle insulin sensitivity 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

49. 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

50. 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

51. 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

52. 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

53. 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

54. 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.

55. 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

56. 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

LATEST ARTICLES

LATEST ARTICLES