Insulin and insulin-like growth factor-I enhance human skeletal muscle protein anabolism during hyperaminoacidemia by different mechanisms (original) (raw)

Abstract

Insulin inhibits proteolysis in human muscle thereby increasing protein anabolism. In contrast, IGF-I promotes muscle protein anabolism principally by stimulating protein synthesis. As increases or decreases of plasma amino acids may affect protein turnover in muscle and also alter the muscle's response to insulin and/or IGF-I, this study was designed to examine the effects of insulin and IGF-I on human muscle protein turnover during hyperaminoacidemia. We measured phenylalanine balance and [3H]-phenylalanine kinetics in both forearms of 22 postabsorptive adults during a continuous [3H] phenylalanine infusion. Measurements were made basally and at 3 and 6 h after beginning a systemic infusion of a balanced amino acid mixture that raised arterial phenylalanine concentration about twofold. Throughout the 6 h, 10 subjects received insulin locally (0.035 mU/min per kg) into one brachial artery while 12 other subjects were given intraaterial IGF-I (100 ng/min per kg) to raise insulin or IGF-I concentrations, respectively, in the infused arm. The contralateral arm in each study served as a simultaneous control for the effects of amino acids (aa) alone. Glucose uptake and lactate release increased in the insulin- and IGF-I-infused forearms (P < 0.01) but did not change in the contralateral (aa alone) forearm in either study. In the aa alone arm in both studies, hyperaminoacidemia reversed the postabsorptive net phenylalanine release by muscle to a net uptake (P < 0.025, for each) due to a stimulation of muscle protein synthesis. In the hormone-infused arms, the addition of either insulin or IGF-I promoted greater positive shifts in phenylalanine balance than the aa alone arm (P < 0.01). With insulin, the enhanced anabolism was due to inhibition of protein degradation (P < 0.02), whereas IGF-I augmented anabolism by a further stimulation of protein synthesis above aa alone (P < 0.02). We conclude that: (a) hyperaminoacidemia specifically stimulates muscle protein synthesis; (b) insulin, even with hyperaminoacidemia, improves muscle protein balance solely by inhibiting proteolysis; and (c) hyperaminoacidemia combined with IGF-I enhances protein synthesis more than either alone.

1722

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Arfvidsson B., Zachrisson H., Möller-Loswick A. C., Hyltander A., Sandström R., Lundholm K. Effect of systemic hyperinsulinemia on amino acid flux across human legs in postabsorptive state. Am J Physiol. 1991 Jan;260(1 Pt 1):E46–E52. doi: 10.1152/ajpendo.1991.260.1.E46. [DOI] [PubMed] [Google Scholar]
  2. Baillie A. G., Garlick P. J. Attenuated responses of muscle protein synthesis to fasting and insulin in adult female rats. Am J Physiol. 1992 Jan;262(1 Pt 1):E1–E5. doi: 10.1152/ajpendo.1992.262.1.E1. [DOI] [PubMed] [Google Scholar]
  3. Barrett E. J., Gelfand R. A. The in vivo study of cardiac and skeletal muscle protein turnover. Diabetes Metab Rev. 1989 Mar;5(2):133–148. doi: 10.1002/dmr.5610050204. [DOI] [PubMed] [Google Scholar]
  4. Barrett E. J., Revkin J. H., Young L. H., Zaret B. L., Jacob R., Gelfand R. A. An isotopic method for measurement of muscle protein synthesis and degradation in vivo. Biochem J. 1987 Jul 1;245(1):223–228. doi: 10.1042/bj2450223. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Bennet W. M., Connacher A. A., Scrimgeour C. M., Jung R. T., Rennie M. J. Euglycemic hyperinsulinemia augments amino acid uptake by human leg tissues during hyperaminoacidemia. Am J Physiol. 1990 Aug;259(2 Pt 1):E185–E194. doi: 10.1152/ajpendo.1990.259.2.E185. [DOI] [PubMed] [Google Scholar]
  6. Biolo G., Declan Fleming R. Y., Wolfe R. R. Physiologic hyperinsulinemia stimulates protein synthesis and enhances transport of selected amino acids in human skeletal muscle. J Clin Invest. 1995 Feb;95(2):811–819. doi: 10.1172/JCI117731. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Boulware S. D., Tamborlane W. V., Matthews L. S., Sherwin R. S. Diverse effects of insulin-like growth factor I on glucose, lipid, and amino acid metabolism. Am J Physiol. 1992 Jan;262(1 Pt 1):E130–E133. doi: 10.1152/ajpendo.1992.262.1.E130. [DOI] [PubMed] [Google Scholar]
  8. 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]
  9. Denne S. C., Liechty E. A., Liu Y. M., Brechtel G., Baron A. D. Proteolysis in skeletal muscle and whole body in response to euglycemic hyperinsulinemia in normal adults. Am J Physiol. 1991 Dec;261(6 Pt 1):E809–E814. doi: 10.1152/ajpendo.1991.261.6.E809. [DOI] [PubMed] [Google Scholar]
  10. Douglas R. G., Gluckman P. D., Ball K., Breier B., Shaw J. H. The effects of infusion of insulinlike growth factor (IGF) I, IGF-II, and insulin on glucose and protein metabolism in fasted lambs. J Clin Invest. 1991 Aug;88(2):614–622. doi: 10.1172/JCI115346. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Elahi D., McAloon-Dyke M., Fukagawa N. K., Sclater A. L., Wong G. A., Shannon R. P., Minaker K. L., Miles J. M., Rubenstein A. H., Vandepol C. J. Effects of recombinant human IGF-I on glucose and leucine kinetics in men. Am J Physiol. 1993 Dec;265(6 Pt 1):E831–E838. doi: 10.1152/ajpendo.1993.265.6.E831. [DOI] [PubMed] [Google Scholar]
  12. Flaim K. E., Kochel P. J., Kira Y., Kobayashi K., Fossel E. T., Jefferson L. S., Morgan H. E. Insulin effects on protein synthesis are independent of glucose and energy metabolism. Am J Physiol. 1983 Jul;245(1):C133–C143. doi: 10.1152/ajpcell.1983.245.1.C133. [DOI] [PubMed] [Google Scholar]
  13. 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]
  14. Frexes-Steed M., Lacy D. B., Collins J., Abumrad N. N. Role of leucine and other amino acids in regulating protein metabolism in vivo. Am J Physiol. 1992 Jun;262(6 Pt 1):E925–E935. doi: 10.1152/ajpendo.1992.262.6.E925. [DOI] [PubMed] [Google Scholar]
  15. Fryburg D. A., Gelfand R. A., Barrett E. J. Growth hormone acutely stimulates forearm muscle protein synthesis in normal humans. Am J Physiol. 1991 Mar;260(3 Pt 1):E499–E504. doi: 10.1152/ajpendo.1991.260.3.E499. [DOI] [PubMed] [Google Scholar]
  16. Fryburg D. A. Insulin-like growth factor I exerts growth hormone- and insulin-like actions on human muscle protein metabolism. Am J Physiol. 1994 Aug;267(2 Pt 1):E331–E336. doi: 10.1152/ajpendo.1994.267.2.E331. [DOI] [PubMed] [Google Scholar]
  17. 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]
  18. Fukagawa N. K., Minaker K. L., Young V. R., Matthews D. E., Bier D. M., Rowe J. W. Leucine metabolism in aging humans: effect of insulin and substrate availability. Am J Physiol. 1989 Feb;256(2 Pt 1):E288–E294. doi: 10.1152/ajpendo.1989.256.2.E288. [DOI] [PubMed] [Google Scholar]
  19. Fukagawa N. K., Minaker K. L., Young V. R., Rowe J. W. Insulin dose-dependent reductions in plasma amino acids in man. Am J Physiol. 1986 Jan;250(1 Pt 1):E13–E17. doi: 10.1152/ajpendo.1986.250.1.E13. [DOI] [PubMed] [Google Scholar]
  20. Fuller S. J., Mynett J. R., Sugden P. H. Stimulation of cardiac protein synthesis by insulin-like growth factors. Biochem J. 1992 Feb 15;282(Pt 1):85–90. doi: 10.1042/bj2820085. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Garlick P. J., Fern M., Preedy V. R. The effect of insulin infusion and food intake on muscle protein synthesis in postabsorptive rats. Biochem J. 1983 Mar 15;210(3):669–676. doi: 10.1042/bj2100669. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Garlick P. J., Grant I. Amino acid infusion increases the sensitivity of muscle protein synthesis in vivo to insulin. Effect of branched-chain amino acids. Biochem J. 1988 Sep 1;254(2):579–584. doi: 10.1042/bj2540579. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Gelfand R. A., Barrett E. J. Effect of physiologic hyperinsulinemia on skeletal muscle protein synthesis and breakdown in man. J Clin Invest. 1987 Jul;80(1):1–6. doi: 10.1172/JCI113033. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Gelfand R. A., Glickman M. G., Castellino P., Louard R. J., DeFronzo R. A. Measurement of L-[1-14C]leucine kinetics in splanchnic and leg tissues in humans. Effect of amino acid infusion. Diabetes. 1988 Oct;37(10):1365–1372. doi: 10.2337/diab.37.10.1365. [DOI] [PubMed] [Google Scholar]
  25. Harper J. M., Soar J. B., Buttery P. J. Changes in protein metabolism of ovine primary muscle cultures on treatment with growth hormone, insulin, insulin-like growth factor I or epidermal growth factor. J Endocrinol. 1987 Jan;112(1):87–96. doi: 10.1677/joe.0.1120087. [DOI] [PubMed] [Google Scholar]
  26. Heslin M. J., Newman E., Wolf R. F., Pisters P. W., Brennan M. F. Effect of hyperinsulinemia on whole body and skeletal muscle leucine carbon kinetics in humans. Am J Physiol. 1992 Jun;262(6 Pt 1):E911–E918. doi: 10.1152/ajpendo.1992.262.6.E911. [DOI] [PubMed] [Google Scholar]
  27. Jefferson L. S. Lilly Lecture 1979: role of insulin in the regulation of protein synthesis. Diabetes. 1980 Jun;29(6):487–496. doi: 10.2337/diab.29.6.487. [DOI] [PubMed] [Google Scholar]
  28. Jefferson L. S., Rannels D. E., Munger B. L., Morgan H. E. Insulin in the regulation of protein turnover in heart and skeletal muscle. Fed Proc. 1974 Apr;33(4):1098–1104. [PubMed] [Google Scholar]
  29. Koea J. B., Douglas R. G., Breier B. H., Shaw J. H., Gluckman P. D. Synergistic effect of insulin-like growth factor-I administration on the protein-sparing effects of total parenteral nutrition in fasted lambs. Endocrinology. 1992 Aug;131(2):643–648. doi: 10.1210/endo.131.2.1639012. [DOI] [PubMed] [Google Scholar]
  30. Laager R., Ninnis R., Keller U. Comparison of the effects of recombinant human insulin-like growth factor-I and insulin on glucose and leucine kinetics in humans. J Clin Invest. 1993 Oct;92(4):1903–1909. doi: 10.1172/JCI116783. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Louard R. J., Fryburg D. A., Gelfand R. A., Barrett E. J. Insulin sensitivity of protein and glucose metabolism in human forearm skeletal muscle. J Clin Invest. 1992 Dec;90(6):2348–2354. doi: 10.1172/JCI116124. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. McNulty P. H., Young L. H., Barrett E. J. Response of rat heart and skeletal muscle protein in vivo to insulin and amino acid infusion. Am J Physiol. 1993 Jun;264(6 Pt 1):E958–E965. doi: 10.1152/ajpendo.1993.264.6.E958. [DOI] [PubMed] [Google Scholar]
  33. McNurlan M. A., Essén P., Thorell A., Calder A. G., Anderson S. E., Ljungqvist O., Sandgren A., Grant I., Tjäder I., Ballmer P. E. Response of protein synthesis in human skeletal muscle to insulin: an investigation with L-[2H5]phenylalanine. Am J Physiol. 1994 Jul;267(1 Pt 1):E102–E108. doi: 10.1152/ajpendo.1994.267.1.E102. [DOI] [PubMed] [Google Scholar]
  34. Monier S., Le Cam A., Le Marchand-Brustel Y. Insulin and insulin-like growth factor I. Effects on protein synthesis in isolated muscles from lean and goldthioglucose-obese mice. Diabetes. 1983 May;32(5):392–397. doi: 10.2337/diab.32.5.392. [DOI] [PubMed] [Google Scholar]
  35. Morgan H. E., Earl D. C., Broadus A., Wolpert E. B., Giger K. E., Jefferson L. S. Regulation of protein synthesis in heart muscle. I. Effect of amino acid levels on protein synthesis. J Biol Chem. 1971 Apr 10;246(7):2152–2162. [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. Möller-Loswick A. C., Zachrisson H., Hyltander A., Körner U., Matthews D. E., Lundholm K. Insulin selectively attenuates breakdown of nonmyofibrillar proteins in peripheral tissues of normal men. Am J Physiol. 1994 Apr;266(4 Pt 1):E645–E652. doi: 10.1152/ajpendo.1994.266.4.E645. [DOI] [PubMed] [Google Scholar]
  38. 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]
  39. Pacy P. J., Garrow J. S., Ford G. C., Merritt H., Halliday D. Influence of amino acid administration on whole-body leucine kinetics and resting metabolic rate in postabsorptive normal subjects. Clin Sci (Lond) 1988 Sep;75(3):225–231. doi: 10.1042/cs0750225. [DOI] [PubMed] [Google Scholar]
  40. Russell-Jones D. L., Umpleby A. M., Hennessy T. R., Bowes S. B., Shojaee-Moradie F., Hopkins K. D., Jackson N. C., Kelly J. M., Jones R. H., Sönksen P. H. Use of a leucine clamp to demonstrate that IGF-I actively stimulates protein synthesis in normal humans. Am J Physiol. 1994 Oct;267(4 Pt 1):E591–E598. doi: 10.1152/ajpendo.1994.267.4.E591. [DOI] [PubMed] [Google Scholar]
  41. Tauveron I., Larbaud D., Champredon C., Debras E., Tesseraud S., Bayle G., Bonnet Y., Thiéblot P., Grizard J. Effect of hyperinsulinemia and hyperaminoacidemia on muscle and liver protein synthesis in lactating goats. Am J Physiol. 1994 Dec;267(6 Pt 1):E877–E885. doi: 10.1152/ajpendo.1994.267.6.E877. [DOI] [PubMed] [Google Scholar]
  42. Tessari P., Inchiostro S., Biolo G., Vincenti E., Sabadin L. Effects of acute systemic hyperinsulinemia on forearm muscle proteolysis in healthy man. J Clin Invest. 1991 Jul;88(1):27–33. doi: 10.1172/JCI115287. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Tessari P., Trevisan R., Inchiostro S., Biolo G., Nosadini R., De Kreutzenberg S. V., Duner E., Tiengo A., Crepaldi G. Dose-response curves of effects of insulin on leucine kinetics in humans. Am J Physiol. 1986 Sep;251(3 Pt 1):E334–E342. doi: 10.1152/ajpendo.1986.251.3.E334. [DOI] [PubMed] [Google Scholar]
  44. Tomas F. M., Knowles S. E., Owens P. C., Read L. C., Chandler C. S., Gargosky S. E., Ballard F. J. Effects of full-length and truncated insulin-like growth factor-I on nitrogen balance and muscle protein metabolism in nitrogen-restricted rats. J Endocrinol. 1991 Jan;128(1):97–105. doi: 10.1677/joe.0.1280097. [DOI] [PubMed] [Google Scholar]
  45. Turkalj I., Keller U., Ninnis R., Vosmeer S., Stauffacher W. Effect of increasing doses of recombinant human insulin-like growth factor-I on glucose, lipid, and leucine metabolism in man. J Clin Endocrinol Metab. 1992 Nov;75(5):1186–1191. doi: 10.1210/jcem.75.5.1430077. [DOI] [PubMed] [Google Scholar]
  46. Venerando R., Miotto G., Kadowaki M., Siliprandi N., Mortimore G. E. Multiphasic control of proteolysis by leucine and alanine in the isolated rat hepatocyte. Am J Physiol. 1994 Feb;266(2 Pt 1):C455–C461. doi: 10.1152/ajpcell.1994.266.2.C455. [DOI] [PubMed] [Google Scholar]
  47. Watt P. W., Lindsay Y., Scrimgeour C. M., Chien P. A., Gibson J. N., Taylor D. J., Rennie M. J. Isolation of aminoacyl-tRNA and its labeling with stable-isotope tracers: Use in studies of human tissue protein synthesis. Proc Natl Acad Sci U S A. 1991 Jul 1;88(13):5892–5896. doi: 10.1073/pnas.88.13.5892. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Young L. H., Stirewalt W., McNulty P. H., Revkin J. H., Barrett E. J. Effect of insulin on rat heart and skeletal muscle phenylalanyl-tRNA labeling and protein synthesis in vivo. Am J Physiol. 1994 Aug;267(2 Pt 1):E337–E342. doi: 10.1152/ajpendo.1994.267.2.E337. [DOI] [PubMed] [Google Scholar]