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. 1996 Jul 1;98(1):90–99. doi: 10.1172/JCI118782

Evidence for a catabolic role of glucagon during an amino acid load.

M R Charlton 1, D B Adey 1, K S Nair 1
PMCID: PMC507404  PMID: 8690809

Abstract

Despite the strong association between protein catabolic conditions and hyperglucagonemia, and enhanced glucagon secretion by amino acids (AA), glucagon's effects on protein metabolism remain less clear than on glucose metabolism. To clearly define glucagon's catabolic effect on protein metabolism during AA load, we studied the effects of glucagon on circulating AA and protein dynamics in six healthy subjects. Five protocols were performed in each subject using somatostatin to inhibit the secretion of insulin, glucagon, and growth hormone (GH) and selectively replacing these hormones in different protocols. Total AA concentration was the highest when glucagon, insulin, and GH were low. Selective increase of glucagon levels prevented this increment in AA. Addition of high levels of insulin and GH to high glucagon had no effect on total AA levels, although branched chain AA levels declined. Glucagon mostly decreased glucogenic AA and enhanced glucose production. Endogenous leucine flux, reflecting proteolysis, decreased while leucine oxidation increased in protocols where AA were infused and these changes were unaffected by the hormones. Nonoxidative leucine flux reflecting protein synthesis was stimulated by AA, but high glucagon attenuated this effect. Addition of GH and insulin partially reversed the inhibitory effect of glucagon on protein synthesis. We conclude that glucagon is the pivotal hormone in amino acid disposal during an AA load and, by reducing the availability of AA, glucagon inhibits protein synthesis stimulated by AA. These data provide further support for a catabolic role of glucagon at physiological concentrations.

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Selected References

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  1. Abumrad N. N., Rabin D., Diamond M. P., Lacy W. W. Use of a heated superficial hand vein as an alternative site for the measurement of amino acid concentrations and for the study of glucose and alanine kinetics in man. Metabolism. 1981 Sep;30(9):936–940. doi: 10.1016/0026-0495(81)90074-3. [DOI] [PubMed] [Google Scholar]
  2. Almdal T. P., Vilstrup H. Exogenous hyperglucagonaemia in insulin controlled diabetic rats increases urea excretion and nitrogen loss from organs. Diabetologia. 1988 Nov;31(11):836–841. doi: 10.1007/BF00277487. [DOI] [PubMed] [Google Scholar]
  3. Bier D. M., Arnold K. J., Sherman W. R., Holland W. H., Holmes W. F., Kipnis D. M. In-vivo measurement of glucose and alanine metabolism with stable isotopic tracers. Diabetes. 1977 Nov;26(11):1005–1015. doi: 10.2337/diab.26.11.1005. [DOI] [PubMed] [Google Scholar]
  4. Blackard W. G., Nelson N. C., Andrews S. S. Portal and peripheral vein immunoreactive glucagon concentrations after arginine or glucose infusions. Diabetes. 1974 Mar;23(3):199–202. doi: 10.2337/diab.23.3.199. [DOI] [PubMed] [Google Scholar]
  5. Block K. P., Heywood B. W., Buse M. G., Harper A. E. Activation of rat liver branched-chain 2-oxo acid dehydrogenase in vivo by glucagon and adrenaline. Biochem J. 1985 Dec 1;232(2):593–597. doi: 10.1042/bj2320593. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Boden G., Master R. W., Rezvani I., Palmer J. P., Lobe T. E., Owen O. E. Glucagon deficiency and hyperaminoacidemia after total pancreatectomy. J Clin Invest. 1980 Mar;65(3):706–716. doi: 10.1172/JCI109717. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Boden G., Rezvani I., Owen O. E. Effects of glucagon on plasma amino acids. J Clin Invest. 1984 Mar;73(3):785–793. doi: 10.1172/JCI111272. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Boden G., Tappy L., Jadali F., Hoeldtke R. D., Rezvani I., Owen O. E. Role of glucagon in disposal of an amino acid load. Am J Physiol. 1990 Aug;259(2 Pt 1):E225–E232. doi: 10.1152/ajpendo.1990.259.2.E225. [DOI] [PubMed] [Google Scholar]
  9. Brockman R. P., Bergman E. N. Effect of glucagon on plasma alanine and glutamine metabolism and hepatic gluconeogenesis in sheep. Am J Physiol. 1975 Jun;228(6):1628–1633. doi: 10.1152/ajplegacy.1975.228.6.1627. [DOI] [PubMed] [Google Scholar]
  10. Cahill G. F., Jr The Banting Memorial Lecture 1971. Physiology of insulin in man. Diabetes. 1971 Dec;20(12):785–799. doi: 10.2337/diab.20.12.785. [DOI] [PubMed] [Google Scholar]
  11. Calles-Escandón J. Insulin dissociates hepatic glucose cycling and glucagon-induced thermogenesis in man. Metabolism. 1994 Aug;43(8):1000–1005. doi: 10.1016/0026-0495(94)90180-5. [DOI] [PubMed] [Google Scholar]
  12. Castellino P., Luzi L., Simonson D. C., Haymond M., DeFronzo R. A. Effect of insulin and plasma amino acid concentrations on leucine metabolism in man. Role of substrate availability on estimates of whole body protein synthesis. J Clin Invest. 1987 Dec;80(6):1784–1793. doi: 10.1172/JCI113272. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Copeland K. C., Kenney F. A., Nair K. S. Heated dorsal hand vein sampling for metabolic studies: a reappraisal. Am J Physiol. 1992 Nov;263(5 Pt 1):E1010–E1014. doi: 10.1152/ajpendo.1992.263.5.E1010. [DOI] [PubMed] [Google Scholar]
  14. Copeland K. C., Nair K. S. Acute growth hormone effects on amino acid and lipid metabolism. J Clin Endocrinol Metab. 1994 May;78(5):1040–1047. doi: 10.1210/jcem.78.5.8175957. [DOI] [PubMed] [Google Scholar]
  15. Couet C., Fukagawa N. K., Matthews D. E., Bier D. M., Young V. R. Plasma amino acid kinetics during acute states of glucagon deficiency and excess in healthy adults. Am J Physiol. 1990 Jan;258(1 Pt 1):E78–E85. doi: 10.1152/ajpendo.1990.258.1.E78. [DOI] [PubMed] [Google Scholar]
  16. Fehlmann M., Le Cam A., Freychet P. Insulin and glucagon stimulation of amino acid transport in isolated rat hepatocytes. Synthesis of a high affinity component of transport. J Biol Chem. 1979 Oct 25;254(20):10431–10437. [PubMed] [Google Scholar]
  17. Flakoll P. J., Borel M. J., Wentzel L. S., Williams P. E., Lacy D. B., Abumrad N. N. The role of glucagon in the control of protein and amino acid metabolism in vivo. Metabolism. 1994 Dec;43(12):1509–1516. doi: 10.1016/0026-0495(94)90009-4. [DOI] [PubMed] [Google Scholar]
  18. Flakoll P. J., Kulaylat M., Frexes-Steed M., Hourani H., Brown L. L., Hill J. O., Abumrad N. N. Amino acids augment insulin's suppression of whole body proteolysis. Am J Physiol. 1989 Dec;257(6 Pt 1):E839–E847. doi: 10.1152/ajpendo.1989.257.6.E839. [DOI] [PubMed] [Google Scholar]
  19. Fukagawa N. K., Minaker K. L., Rowe J. W., Goodman M. N., Matthews D. E., Bier D. M., Young V. R. Insulin-mediated reduction of whole body protein breakdown. Dose-response effects on leucine metabolism in postabsorptive men. J Clin Invest. 1985 Dec;76(6):2306–2311. doi: 10.1172/JCI112240. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Halliday D., Read W. W. Mass spectrometric assay of stable isotopic enrichment for the estimation of protein turnover in man. Proc Nutr Soc. 1981 Sep;40(3):321–324. doi: 10.1079/pns19810048. [DOI] [PubMed] [Google Scholar]
  21. Hartl W. H., Miyoshi H., Jahoor F., Klein S., Elahi D., Wolfe R. R. Bradykinin attenuates glucagon-induced leucine oxidation in humans. Am J Physiol. 1990 Aug;259(2 Pt 1):E239–E245. doi: 10.1152/ajpendo.1990.259.2.E239. [DOI] [PubMed] [Google Scholar]
  22. Hill D. W., Walters F. H., Wilson T. D., Stuart J. D. High performance liquid chromatographic determination of amino acids in the picomole range. Anal Chem. 1979 Jul;51(8):1338–1341. doi: 10.1021/ac50044a055. [DOI] [PubMed] [Google Scholar]
  23. Jaspan J. B., Polonsky K. S., Lewis M., Pensler J., Pugh W., Moossa A. R., Rubenstein A. H. Hepatic metabolism of glucagon in the dog: contribution of the liver to overall metabolic disposal of glucagon. Am J Physiol. 1981 Mar;240(3):E233–E244. doi: 10.1152/ajpendo.1981.240.3.E233. [DOI] [PubMed] [Google Scholar]
  24. Jaspan J. B., Ruddick J., Rayfield E. Transhepatic glucagon gradients in man: evidence for glucagon extraction by human liver. J Clin Endocrinol Metab. 1984 Feb;58(2):287–292. doi: 10.1210/jcem-58-2-287. [DOI] [PubMed] [Google Scholar]
  25. Jenssen T., Nurjhan N., Consoli A., Gerich J. E. Failure of substrate-induced gluconeogenesis to increase overall glucose appearance in normal humans. Demonstration of hepatic autoregulation without a change in plasma glucose concentration. J Clin Invest. 1990 Aug;86(2):489–497. doi: 10.1172/JCI114735. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Kelley D. S., Shull J. D., Potter V. R. Hormonal regulation of amino acid transport and cAMP production in monolayer cultures of rat hepatocytes. J Cell Physiol. 1980 Apr;103(1):159–168. doi: 10.1002/jcp.1041030120. [DOI] [PubMed] [Google Scholar]
  27. Louard R. J., Barrett E. J., Gelfand R. A. Effect of infused branched-chain amino acids on muscle and whole-body amino acid metabolism in man. Clin Sci (Lond) 1990 Nov;79(5):457–466. doi: 10.1042/cs0790457. [DOI] [PubMed] [Google Scholar]
  28. Luzi L., Castellino P., Simonson D. C., Petrides A. S., DeFronzo R. A. Leucine metabolism in IDDM. Role of insulin and substrate availability. Diabetes. 1990 Jan;39(1):38–48. doi: 10.2337/diacare.39.1.38. [DOI] [PubMed] [Google Scholar]
  29. Mallet L. E., Exton J. H., Park C. R. Control of gluconeogenesis from amino acids in the perfused rat liver. J Biol Chem. 1969 Oct 25;244(20):5713–5723. [PubMed] [Google Scholar]
  30. Mallinson C. N., Bloom S. R., Warin A. P., Salmon P. R., Cox B. A glucagonoma syndrome. Lancet. 1974 Jul 6;2(7871):1–5. doi: 10.1016/s0140-6736(74)91343-9. [DOI] [PubMed] [Google Scholar]
  31. Matthews D. E., Bier D. M., Rennie M. J., Edwards R. H., Halliday D., Millward D. J., Clugston G. A. Regulation of leucine metabolism in man: a stable isotope study. Science. 1981 Dec 4;214(4525):1129–1131. doi: 10.1126/science.7302583. [DOI] [PubMed] [Google Scholar]
  32. Matthews D. E., Motil K. J., Rohrbaugh D. K., Burke J. F., Young V. R., Bier D. M. Measurement of leucine metabolism in man from a primed, continuous infusion of L-[1-3C]leucine. Am J Physiol. 1980 May;238(5):E473–E479. doi: 10.1152/ajpendo.1980.238.5.E473. [DOI] [PubMed] [Google Scholar]
  33. May M. E., Buse M. G. Effects of branched-chain amino acids on protein turnover. Diabetes Metab Rev. 1989 May;5(3):227–245. doi: 10.1002/dmr.5610050303. [DOI] [PubMed] [Google Scholar]
  34. McCullough A. J., Mullen K. D., Tavill A. S., Kalhan S. C. In vivo differences between the turnover rates of leucine and leucine's ketoacid in stable cirrhosis. Gastroenterology. 1992 Aug;103(2):571–578. doi: 10.1016/0016-5085(92)90849-t. [DOI] [PubMed] [Google Scholar]
  35. Meguid M. M., Brennan M. F., Aoki T. T., Muller W. A., Ball M. R., Moore F. D. Hormone-substrate interrelationships following trauma. Arch Surg. 1974 Dec;109(6):776–783. doi: 10.1001/archsurg.1974.01360060046013. [DOI] [PubMed] [Google Scholar]
  36. Mortimore G. E., Pösö A. R., Lardeux B. R. Mechanism and regulation of protein degradation in liver. Diabetes Metab Rev. 1989 Feb;5(1):49–70. doi: 10.1002/dmr.5610050105. [DOI] [PubMed] [Google Scholar]
  37. Nair K. S., Ford G. C., Ekberg K., Fernqvist-Forbes E., Wahren J. Protein dynamics in whole body and in splanchnic and leg tissues in type I diabetic patients. J Clin Invest. 1995 Jun;95(6):2926–2937. doi: 10.1172/JCI118000. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Nair K. S., Garrow J. S., Ford C., Mahler R. F., Halliday D. Effect of poor diabetic control and obesity on whole body protein metabolism in man. Diabetologia. 1983 Nov;25(5):400–403. doi: 10.1007/BF00282518. [DOI] [PubMed] [Google Scholar]
  39. Nair K. S., Halliday D., Matthews D. E., Welle S. L. Hyperglucagonemia during insulin deficiency accelerates protein catabolism. Am J Physiol. 1987 Aug;253(2 Pt 1):E208–E213. doi: 10.1152/ajpendo.1987.253.2.E208. [DOI] [PubMed] [Google Scholar]
  40. Nair K. S. Hyperglucagonemia increases resting metabolic rate in man during insulin deficiency. J Clin Endocrinol Metab. 1987 May;64(5):896–901. doi: 10.1210/jcem-64-5-896. [DOI] [PubMed] [Google Scholar]
  41. Nair K. S., Matthews D. E., Welle S. L., Braiman T. Effect of leucine on amino acid and glucose metabolism in humans. Metabolism. 1992 Jun;41(6):643–648. doi: 10.1016/0026-0495(92)90057-h. [DOI] [PubMed] [Google Scholar]
  42. Nair K. S., Schwartz R. G., Welle S. Leucine as a regulator of whole body and skeletal muscle protein metabolism in humans. Am J Physiol. 1992 Nov;263(5 Pt 1):E928–E934. doi: 10.1152/ajpendo.1992.263.5.E928. [DOI] [PubMed] [Google Scholar]
  43. Rocha D. M., Santeusanio F., Faloona G. R., Unger R. H. Abnormal pancreatic alpha-cell function in bacterial infections. N Engl J Med. 1973 Apr 5;288(14):700–703. doi: 10.1056/NEJM197304052881402. [DOI] [PubMed] [Google Scholar]
  44. Roth E., Mühlbacher F., Karner J., Hamilton G., Funovics J. Free amino acid levels in muscle and liver of a patient with glucagonoma syndrome. Metabolism. 1987 Jan;36(1):7–13. doi: 10.1016/0026-0495(87)90055-2. [DOI] [PubMed] [Google Scholar]
  45. Russell R. C., Walker C. J., Bloom S. R. Hyperglucagonaemia in the surgical patient. Br Med J. 1975 Jan 4;1(5948):10–12. doi: 10.1136/bmj.1.5948.10. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Schwenk W. F., Beaufrere B., Haymond M. W. Use of reciprocal pool specific activities to model leucine metabolism in humans. Am J Physiol. 1985 Dec;249(6 Pt 1):E646–E650. doi: 10.1152/ajpendo.1985.249.6.E646. [DOI] [PubMed] [Google Scholar]
  47. Silva S. V., Mercer J. R. The control of protein degradation in monolayer cultures of cat hepatocytes. Int J Biochem. 1992 Oct;24(10):1651–1656. doi: 10.1016/0020-711x(92)90183-2. [DOI] [PubMed] [Google Scholar]
  48. Tessari P., Inchiostro S., Biolo G., Trevisan R., Fantin G., Marescotti M. C., Iori E., Tiengo A., Crepaldi G. Differential effects of hyperinsulinemia and hyperaminoacidemia on leucine-carbon metabolism in vivo. Evidence for distinct mechanisms in regulation of net amino acid deposition. J Clin Invest. 1987 Apr;79(4):1062–1069. doi: 10.1172/JCI112919. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Tessari P., Nosadini R., Trevisan R., De Kreutzenberg S. V., Inchiostro S., Duner E., Biolo G., Marescotti M. C., Tiengo A., Crepaldi G. 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 Jun;77(6):1797–1804. doi: 10.1172/JCI112504. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Welle S., Nair K. S. Relationship of resting metabolic rate to body composition and protein turnover. Am J Physiol. 1990 Jun;258(6 Pt 1):E990–E998. doi: 10.1152/ajpendo.1990.258.6.E990. [DOI] [PubMed] [Google Scholar]
  51. Wilmore D. W., Lindsey C. A., Moyland J. A., Faloona G. R., Pruitt B. A., Unger R. H. Hyperglucagonaemia after burns. Lancet. 1974 Jan 19;1(7847):73–75. doi: 10.1016/s0140-6736(74)92290-9. [DOI] [PubMed] [Google Scholar]
  52. Wolfe R. R., Goodenough R. D., Wolfe M. H., Royle G. T., Nadel E. R. Isotopic analysis of leucine and urea metabolism in exercising humans. J Appl Physiol Respir Environ Exerc Physiol. 1982 Feb;52(2):458–466. doi: 10.1152/jappl.1982.52.2.458. [DOI] [PubMed] [Google Scholar]
  53. Woodside K. H., Ward W. F., Mortimore G. E. Effects of glucagon on general protein degradation and synthesis in perfused rat liver. J Biol Chem. 1974 Sep 10;249(17):5458–5463. [PubMed] [Google Scholar]

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