The Complex Role of Branched Chain Amino Acids in Diabetes and Cancer

The obesity and diabetes epidemics are continuing to spread across the globe. There is increasing evidence that diabetes leads to a significantly higher risk for certain types of cancer. Both diabetes and cancer are characterized by severe metabolic perturbations and the branched chain amino acids (BCAAs) appear to play a significant role in both of these diseases. These essential amino acids participate in a wide variety of metabolic pathways, but it is now recognized that they are also critical regulators of a number of cell signaling pathways. An elevation in branched chain amino acids has recently been shown to be significantly correlated with insulin resistance and the future development of diabetes. In cancer, the normal demands for BCAAs are complicated by the conflicting needs of the tumor and the host. The severe muscle wasting syndrome experience by many cancer patients, known as cachexia, has motivated the use of BCAA supplementation. The desired improvement in muscle mass must be balanced by the need to avoid providing materials for tumor proliferation. A better understanding of the complex functions of BCAAs could lead to their use as biomarkers of the progression of certain cancers in diabetic patients.

[1]  G. Thomas,et al.  Nutrient overload, insulin resistance, and ribosomal protein S6 kinase 1, S6K1. , 2006, Cell metabolism.

[2]  H. Moriwaki,et al.  Activation of hepatic branched-chain α-keto acid dehydrogenase complex by tumor necrosis factor-α in rats , 2005 .

[3]  E. Tai,et al.  Insulin resistance is associated with a metabolic profile of altered protein metabolism in Chinese and Asian-Indian men , 2010, Diabetologia.

[4]  P. Felig,et al.  Plasma amino acid levels and insulin secretion in obesity. , 1970, The New England journal of medicine.

[5]  D. Leroith,et al.  Epidemiology and Molecular Mechanisms Tying Obesity, Diabetes, and the Metabolic Syndrome With Cancer , 2013, Diabetes Care.

[6]  Christopher G Proud,et al.  mTORC1 signaling: what we still don't know. , 2011, Journal of molecular cell biology.

[7]  A. Tee,et al.  Leucine and mTORC1: a complex relationship. , 2012, American journal of physiology. Endocrinology and metabolism.

[8]  H. Tsubouchi Hepatocyte growth factor for liver disease , 1999, Hepatology.

[9]  E. Barrett,et al.  Amino acids regulate skeletal muscle PHAS-I and p70 S6-kinase phosphorylation independently of insulin. , 2000, American journal of physiology. Endocrinology and metabolism.

[10]  H. Eagle,et al.  Nutrition needs of mammalian cells in tissue culture. , 1955, Science.

[11]  B. Carstensen,et al.  Diabetes and cancer (1): evaluating the temporal relationship between type 2 diabetes and cancer incidence , 2012, Diabetologia.

[12]  O. Warburg über den Stoffwechsel der Carcinomzelle , 1925, Klinische Wochenschrift.

[13]  C. Thompson,et al.  Glutamine addiction: a new therapeutic target in cancer. , 2010, Trends in biochemical sciences.

[14]  Peter Nowotny,et al.  Mechanism of amino acid-induced skeletal muscle insulin resistance in humans. , 2002, Diabetes.

[15]  N. Izumi,et al.  [Long time oral supplementation with branched-chain amino acids improves survival and decreases recurrences in patients with hepatocellular carcinoma]. , 2008, Nihon Shokakibyo Gakkai zasshi = The Japanese journal of gastro-enterology.

[16]  S. John,et al.  The impact of cow's milk-mediated mTORC1-signaling in the initiation and progression of prostate cancer , 2012, Nutrition & Metabolism.

[17]  J. Norton,et al.  Fasting plasma amino acid levels in cancer patients , 1985, Cancer.

[18]  Terho Lehtimäki,et al.  Branched-Chain and Aromatic Amino Acids Are Predictors of Insulin Resistance in Young Adults , 2013, Diabetes Care.

[19]  Y. Inoue,et al.  Leucine stimulates the secretion of hepatocyte growth factor by hepatic stellate cells. , 2002, Biochemical and biophysical research communications.

[20]  M. Holeček,et al.  Effect of alanyl-glutamine on leucine and protein metabolism in irradiated rats , 2002, Amino Acids.

[21]  Eyal Gottlieb,et al.  Metabolic transformation in cancer. , 2009, Carcinogenesis.

[22]  R. Harris,et al.  Regulation of the branched-chain alpha-ketoacid dehydrogenase and elucidation of a molecular basis for maple syrup urine disease. , 1990, Advances in enzyme regulation.

[23]  V. Baracos,et al.  Investigations of branched-chain amino acids and their metabolites in animal models of cancer. , 2006, The Journal of nutrition.

[24]  R. Deberardinis,et al.  Beyond aerobic glycolysis: Transformed cells can engage in glutamine metabolism that exceeds the requirement for protein and nucleotide synthesis , 2007, Proceedings of the National Academy of Sciences.

[25]  Claudio R. Santos,et al.  A new player in the orchestra of cell growth: SREBP activity is regulated by mTORC1 and contributes to the regulation of cell and organ size. , 2009, Biochemical Society transactions.

[26]  K. Inoki,et al.  TSC2 Mediates Cellular Energy Response to Control Cell Growth and Survival , 2003, Cell.

[27]  J. Avruch,et al.  Amino Acid Sufficiency and mTOR Regulate p70 S6 Kinase and eIF-4E BP1 through a Common Effector Mechanism* , 1998, The Journal of Biological Chemistry.

[28]  Asami Hagiwara,et al.  Branched‐chain amino acids prevent insulin‐induced hepatic tumor cell proliferation by inducing apoptosis through mTORC1 and mTORC2‐dependent mechanisms , 2012, Journal of cellular physiology.

[29]  Susan Cheng,et al.  Metabolite Profiling Identifies Pathways Associated With Metabolic Risk in Humans , 2012, Circulation.

[30]  M. Milburn,et al.  Harnessing the Power of the Immune System to Target Cancer , 2013 .

[31]  E. Calle,et al.  Overweight, obesity and cancer: epidemiological evidence and proposed mechanisms , 2004, Nature Reviews Cancer.

[32]  R. Miller,et al.  Branched-chain amino acid metabolism. , 1984, Annual review of nutrition.

[33]  Anne E Carpenter,et al.  mTOR Complex 1 Regulates Lipin 1 Localization to Control the SREBP Pathway , 2011, Cell.

[34]  A. Goldberg,et al.  Oxidation of leucine by rat skeletal muscle. , 1972, The American journal of physiology.

[35]  H. Moriwaki,et al.  Activation of hepatic branched-chain alpha-keto acid dehydrogenase complex by tumor necrosis factor-alpha in rats. , 2005, Biochemical and biophysical research communications.

[36]  B. Turk,et al.  AMPK phosphorylation of raptor mediates a metabolic checkpoint. , 2008, Molecular cell.

[37]  A. Inui,et al.  Branched-chain amino acids: the best compromise to achieve anabolism? , 2005, Current opinion in clinical nutrition and metabolic care.

[38]  Svati H Shah,et al.  A branched-chain amino acid-related metabolic signature that differentiates obese and lean humans and contributes to insulin resistance. , 2009, Cell metabolism.

[39]  C. Proud,et al.  Nutrient control of TORC1, a cell-cycle regulator. , 2009, Trends in cell biology.

[40]  Yoshiyuki Suzuki,et al.  Inhibitory effect of branched-chain amino acid granules on progression of compensated liver cirrhosis due to hepatitis C virus , 2008, Journal of Gastroenterology.

[41]  Michael J Thun,et al.  Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults. , 2003, The New England journal of medicine.

[42]  N. Hay,et al.  The two TORCs and Akt. , 2007, Developmental cell.

[43]  Masahiko Kato,et al.  Clinical comparison of branched-chain amino acid (l-Leucine, l-Isoleucine, l-Valine) granules and oral nutrition for hepatic insufficiency in patients with decompensated liver cirrhosis (LIV-EN study). , 2005, Hepatology research : the official journal of the Japan Society of Hepatology.

[44]  R. Poon,et al.  Role of branched‐chain amino acids in management of cirrhosis and hepatocellular carcinoma , 2008, Hepatology research : the official journal of the Japan Society of Hepatology.

[45]  C. Stanley,et al.  The structure and allosteric regulation of mammalian glutamate dehydrogenase. , 2012, Archives of biochemistry and biophysics.

[46]  K. Nakao,et al.  Branched‐chain amino acid deficiency stabilizes insulin‐induced vascular endothelial growth factor mRNA in hepatocellular carcinoma cells , 2012, Journal of cellular biochemistry.

[47]  Richard D. Beger,et al.  A Review of Applications of Metabolomics in Cancer , 2013, Metabolites.

[48]  Christian Gieger,et al.  Biomarkers for Type 2 Diabetes and Impaired Fasting Glucose Using a Nontargeted Metabolomics Approach , 2013, Diabetes.

[49]  D. Sabatini,et al.  Regulation of the mTOR complex 1 pathway by nutrients, growth factors, and stress. , 2010, Molecular cell.

[50]  D. Harlan,et al.  Diabetes and Cancer , 2010, Diabetes Care.

[51]  K. Nair,et al.  Assessment of branched-chain amino Acid status and potential for biomarkers. , 2006, The Journal of nutrition.

[52]  V. Mootha,et al.  Circulating branched‐chain amino acid concentrations are associated with obesity and future insulin resistance in children and adolescents , 2013, Pediatric obesity.

[53]  P. Felig,et al.  Splanchnic glucose and amino acid metabolism in obesity. , 1974, The Journal of clinical investigation.

[54]  William E. Kraus,et al.  Relationships Between Circulating Metabolic Intermediates and Insulin Action in Overweight to Obese, Inactive Men and Women , 2009, Diabetes Care.

[55]  M. Tisdale,et al.  Nitrogen excretion in cancer cachexia and its modification by a high fat diet in mice. , 1989, Cancer research.

[56]  L. Moldawer,et al.  Improved protein kinetics and albumin synthesis by branched chain amino acid‐enriched total parenteral nutrition in cancer cachexia: A prospective randomized crossover trial , 1986, Cancer.

[57]  薫 土谷,et al.  分岐鎖アミノ酸(BCAA)長期投与による肝細胞癌再発抑制 , 2008 .

[58]  Joseph R. Bertino,et al.  Prognostic effect of weight loss prior to chemotherapy in cancer patients. Eastern Cooperative Oncology Group. , 1980, The American journal of medicine.

[59]  E. Gottlieb,et al.  Glutaminolysis activates Rag-mTORC1 signaling. , 2012, Molecular cell.

[60]  C. Begg,et al.  Prognostic effect of weight loss prior to chemotherapy in cancer patients. Eastern Cooperative Oncology Group. , 1980, The American journal of medicine.

[61]  M. Tisdale,et al.  Effect of branched-chain amino acids on muscle atrophy in cancer cachexia. , 2007, The Biochemical journal.

[62]  R. Deberardinis,et al.  Q's next: the diverse functions of glutamine in metabolism, cell biology and cancer , 2010, Oncogene.

[63]  K. Takehana,et al.  Branched-chain amino acids improve glucose metabolism in rats with liver cirrhosis. , 2005, American journal of physiology. Gastrointestinal and liver physiology.

[64]  M. Holeček Branched-chain Amino Acid Oxidation in Skeletal Muscle – Physiological and Clinical Importance of its Modulation by Reactant Availability , 2011 .

[65]  Guido Kroemer,et al.  Tumor cell metabolism: cancer's Achilles' heel. , 2008, Cancer cell.

[66]  A. Peters,et al.  Identification of Serum Metabolites Associated With Risk of Type 2 Diabetes Using a Targeted Metabolomic Approach , 2013, Diabetes.

[67]  V. Mootha,et al.  Metabolite profiles and the risk of developing diabetes , 2011, Nature Medicine.

[68]  Ralph J Deberardinis,et al.  Brick by brick: metabolism and tumor cell growth. , 2008, Current opinion in genetics & development.

[69]  T. Kawaguchi,et al.  Branched-chain amino acid-enriched supplementation improves insulin resistance in patients with chronic liver disease. , 2008, International Journal of Molecular Medicine.

[70]  H. Grosse [Diabetes and cancer]. , 1956, Deutsche Zeitschrift fur Verdauungs- und Stoffwechselkrankheiten.

[71]  M. Holeček Relation between glutamine, branched-chain amino acids, and protein metabolism. , 2002, Nutrition.

[72]  K. Inoki,et al.  TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling , 2002, Nature Cell Biology.

[73]  Masahiko Kato,et al.  Effects of oral branched-chain amino acid granules on event-free survival in patients with liver cirrhosis. , 2005, Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association.

[74]  Y. Zick,et al.  Ser/Thr Phosphorylation of IRS Proteins: A Molecular Basis for Insulin Resistance , 2005, Science's STKE.

[75]  P. Felig The glucose-alanine cycle. , 1973, Metabolism: clinical and experimental.

[76]  N. Deutz,et al.  Metabolic changes of cancer cachexia--second of two parts. , 1997, Clinical nutrition.

[77]  S. Kimball,et al.  Signaling pathways and molecular mechanisms through which branched-chain amino acids mediate translational control of protein synthesis. , 2006, The Journal of nutrition.

[78]  G. Blackburn,et al.  Branched chain amino acids as the protein component of parenteral nutrition in cancer cachexia , 1989, The British journal of surgery.

[79]  Gabi Kastenmüller,et al.  Early Metabolic Markers of the Development of Dysglycemia and Type 2 Diabetes and Their Physiological Significance , 2013, Diabetes.

[80]  K. Inoki,et al.  Spatial regulation of the mTORC1 system in amino acids sensing pathway. , 2011, Acta biochimica et biophysica Sinica.

[81]  D. Sabatini,et al.  Ragulator-Rag Complex Targets mTORC1 to the Lysosomal Surface and Is Necessary for Its Activation by Amino Acids , 2010, Cell.

[82]  M. Tisdale Biology of cachexia. , 1997, Journal of the National Cancer Institute.