Skip to main content
PMC home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1987 Jul;80(1):1–6. doi: 10.1172/JCI113033

Effect of physiologic hyperinsulinemia on skeletal muscle protein synthesis and breakdown in man.

R A Gelfand, E J Barrett
PMCID: PMC442193  PMID: 3298320

Abstract

Although insulin stimulates protein synthesis and inhibits protein breakdown in skeletal muscle in vitro, the actual contribution of these actions to its anabolic effects in man remains unknown. Using the forearm perfusion method together with systemic infusion of L-[ring-2,6-3H]phenylalanine and L-[1-14C]leucine, we measured steady state amino acid exchange kinetics across muscle in seven normal males before and in response to a 2-h intraarterial infusion of insulin. Postabsorptively, the muscle disposal (Rd) of phenylalanine (43 +/- 5 nmol/min per 100 ml forearm) and leucine (113 +/- 13) was exceeded by the concomitant muscle production (Ra) of these amino acids (57 +/- 5 and 126 +/- 9 nmol/min per dl, respectively), resulting in their net release from the forearm (-14 +/- 4 and -13 +/- 5 nmol/min per dl, respectively). In response to forearm hyperinsulinemia (124 +/- 11 microU/ml), the net balance of phenylalanine and leucine became positive (9 +/- 3 and 61 +/- 8 nmol/min per dl, respectively (P less than 0.005 vs. basal). Despite the marked increase in net balance, the tissue Rd for both phenylalanine (42 +/- 2) and leucine (124 +/- 9) was unchanged from baseline, while Ra was markedly suppressed (to 33 +/- 5 and 63 +/- 9 nmol/min per dl, respectively, P less than 0.01). Since phenylalanine is not metabolized in muscle (i.e., its only fates are incorporation into or release from protein) these results strongly suggest that in normal man, physiologic elevations in insulin promote net muscle protein anabolism primarily by inhibiting protein breakdown, rather than by stimulating protein synthesis.

Full text

PDF
1

Selected References

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

  1. ANDRES R., CADER G., ZIERLER K. L. The quantitatively minor role of carbohydrate in oxidative metabolism by skeletal muscle in intact man in the basal state; measurements of oxygen and glucose uptake and carbon dioxide and lactate production in the forearm. J Clin Invest. 1956 Jun;35(6):671–682. doi: 10.1172/JCI103324. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. ANDRES R., ZIERLER K. L., ANDERSON H. M., STAINSBY W. N., CADER G., GHRAYYIB A. S., LILIENTHAL J. L., Jr Measurement of blood flow and volume in the forearm of man; with notes on the theory of indicator-dilution and on production of turbulence, hemolysis, and vasodilatation by intra-vascular injection. J Clin Invest. 1954 Apr;33(4):482–504. doi: 10.1172/JCI102919. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. COLES D. R., COOPER K. E., MOTTRAM R. F., OCCLESHAW J. V. The source of blood samples withdrawn from deep forearm veins via catheters passed upstream from the median cubital vein. J Physiol. 1958 Jul 14;142(2):323–328. doi: 10.1113/jphysiol.1958.sp006019. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Clarke J. T., Bier D. M. The conversion of phenylalanine to tyrosine in man. Direct measurement by continuous intravenous tracer infusions of L-[ring-2H5]phenylalanine and L-[1-13C] tyrosine in the postabsorptive state. Metabolism. 1982 Oct;31(10):999–1005. doi: 10.1016/0026-0495(82)90142-1. [DOI] [PubMed] [Google Scholar]
  5. FORKER L. L., CHAIKOFF I. L., ENTENMAN C., TRAVER H. Formation of muscle protein in diabetic dogs, studies with S35 methionine. J Biol Chem. 1951 Jan;188(1):37–48. [PubMed] [Google Scholar]
  6. Frayn K. N., Maycock P. F. Regulation of protein metabolism by a physiological concentration of insulin in mouse soleus and extensor digitorum longus muscles. Effects of starvation and scald injury. Biochem J. 1979 Nov 15;184(2):323–330. doi: 10.1042/bj1840323. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. 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]
  8. Fulks R. M., Li J. B., Goldberg A. L. Effects of insulin, glucose, and amino acids on protein turnover in rat diaphragm. J Biol Chem. 1975 Jan 10;250(1):290–298. [PubMed] [Google Scholar]
  9. Goldberg A. L., Odessey R. Oxidation of amino acids by diaphragms from fed and fasted rats. Am J Physiol. 1972 Dec;223(6):1384–1391. doi: 10.1152/ajplegacy.1972.223.6.1384. [DOI] [PubMed] [Google Scholar]
  10. Halliday D., McKeran R. O. Measurement of muscle protein synthetic rate from serial muscle biopsies and total body protein turnover in man by continuous intravenous infusion of L-(alpha-15N)lysine. Clin Sci Mol Med. 1975 Dec;49(6):581–590. doi: 10.1042/cs0490581. [DOI] [PubMed] [Google Scholar]
  11. Jefferson L. S., Koehler J. O., Morgan H. E. Effect of insulin on protein synthesis in skeletal muscle of an isolated perfused preparation of rat hemicorpus. Proc Natl Acad Sci U S A. 1972 Apr;69(4):816–820. doi: 10.1073/pnas.69.4.816. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Jefferson L. S., Li J. B., Rannels S. R. Regulation by insulin of amino acid release and protein turnover in the perfused rat hemicorpus. J Biol Chem. 1977 Feb 25;252(4):1476–1483. [PubMed] [Google Scholar]
  13. 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]
  14. 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]
  15. Li J. B., Higgins J. E., Jefferson L. S. Changes in protein turnover in skeletal muscle in response to fasting. Am J Physiol. 1979 Mar;236(3):E222–E228. doi: 10.1152/ajpendo.1979.236.3.E222. [DOI] [PubMed] [Google Scholar]
  16. Liang C., Doherty J. U., Faillace R., Maekawa K., Arnold S., Gavras H., Hood W. B., Jr Insulin infusion in conscious dogs. Effects on systemic and coronary hemodynamics, regional blood flows, and plasma catecholamines. J Clin Invest. 1982 Jun;69(6):1321–1336. doi: 10.1172/JCI110572. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Lundholm K., Edström S., Ekman L., Karlberg I., Walker P., Scherstén T. Protein degradation in human skeletal muscle tissue: the effect of insulin, leucine, amino acids and ions. Clin Sci (Lond) 1981 Mar;60(3):319–326. doi: 10.1042/cs0600319. [DOI] [PubMed] [Google Scholar]
  18. Martin A. F., Rabinowitz M., Blough R., Prior G., Zak R. Measurements of half-life of rat cardiac myosin heavy chain with leucyl-tRNA used as precursor pool. J Biol Chem. 1977 May 25;252(10):3422–3429. [PubMed] [Google Scholar]
  19. Matthews D. E., Schwarz H. P., Yang R. D., Motil K. J., Young V. R., Bier D. M. Relationship of plasma leucine and alpha-ketoisocaproate during a L-[1-13C]leucine infusion in man: a method for measuring human intracellular leucine tracer enrichment. Metabolism. 1982 Nov;31(11):1105–1112. doi: 10.1016/0026-0495(82)90160-3. [DOI] [PubMed] [Google Scholar]
  20. Odedra B. R., Dalal S. S., Millward D. J. Muscle protein synthesis in the streptozotocin-diabetic rat. A possible role for corticosterone in the insensitivity to insulin infusion in vivo. Biochem J. 1982 Feb 15;202(2):363–368. doi: 10.1042/bj2020363. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Pain V. M., Garlick P. J. Effect of streptozotocin diabetes and insulin treatment on the rate of protein synthesis in tissues of the rat in vivo. J Biol Chem. 1974 Jul 25;249(14):4510–4514. [PubMed] [Google Scholar]
  22. Pozefsky T., Felig P., Tobin J. D., Soeldner J. S., Cahill G. F., Jr Amino acid balance across tissues of the forearm in postabsorptive man. Effects of insulin at two dose levels. J Clin Invest. 1969 Dec;48(12):2273–2282. doi: 10.1172/JCI106193. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Rannels D. E., Li J. B., Morgan H. E., Jefferson L. S. Evaluation of hormone effects on protein turnover in isolated perfused organs. Methods Enzymol. 1975;37:238–250. doi: 10.1016/s0076-6879(75)37020-1. [DOI] [PubMed] [Google Scholar]
  24. Rannels D. E., Wartell S. A., Watkins C. A. The measurement of protein synthesis in biological systems. Life Sci. 1982 May 17;30(20):1679–1690. doi: 10.1016/0024-3205(82)90300-9. [DOI] [PubMed] [Google Scholar]
  25. Rennie M. J., Edwards R. H., Halliday D., Matthews D. E., Wolman S. L., Millward D. J. Muscle protein synthesis measured by stable isotope techniques in man: the effects of feeding and fasting. Clin Sci (Lond) 1982 Dec;63(6):519–523. doi: 10.1042/cs0630519. [DOI] [PubMed] [Google Scholar]
  26. Sloan G. M., Norton J. A., Brennan M. F. Influence of diabetes mellitus and insulin treatment on protein turnover in the rat. J Surg Res. 1980 May;28(5):442–448. doi: 10.1016/0022-4804(80)90108-0. [DOI] [PubMed] [Google Scholar]
  27. Stirewalt W. S., Low R. B., Slaiby J. M. Insulin sensitivity and responsiveness of epitrochlearis and soleus muscles from fed and starved rats. Recognition of differential changes in insulin sensitivities of protein synthesis and glucose incorporation into glycogen. Biochem J. 1985 Apr 15;227(2):355–362. doi: 10.1042/bj2270355. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. 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]
  29. 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]
  30. Tsalikian E., Howard C., Gerich J. E., Haymond M. W. Increased leucine flux in short-term fasted human subjects: evidence for increased proteolysis. Am J Physiol. 1984 Sep;247(3 Pt 1):E323–E327. doi: 10.1152/ajpendo.1984.247.3.E323. [DOI] [PubMed] [Google Scholar]
  31. Williams I. H., Sugden P. H., Morgan H. E. Use of aromatic amino acids as monitors of protein turnover. Am J Physiol. 1981 Jun;240(6):E677–E681. doi: 10.1152/ajpendo.1981.240.6.E677. [DOI] [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES