Comprehensive Physiology Wiley Online Library

The Regulation of Amino Acid and Protein Metabolism by Growth Hormone

Full Article on Wiley Online Library



Abstract

The sections in this article are:

1 In Vitro Actions of Growth Hormone and Insulin‐Like Growth Factor I on Protein Metabolism
1.1 Effects of Growth Hormone In Vitro
1.2 Effects of Insulin‐Like Growth Factor I In Vitro
1.3 In Vitro Actions of Growth Hormone and Insulin‐Like Growth Factor I on Protein Degradation
2 In vivo Actions of Growth Hormone and Insulin‐Like Growth Factor I on Protein Metabolism
2.1 Effects of Growth Hormone In Vivo
2.2 Effects of Insulin‐Like Growth Factor I In Vivo
3 Comparison of the Actions of Growth Hormone, Insulin‐Like Growth Factor I, and Insulin on Protein Metabolism in vivo
4 Interactions of Growth Hormone with Gonadal Steroids
5 Growth Hormone and Insulin‐Like Growth Factor I as Therapy in Catabolic States
6 Summary
Figure 1. Figure 1.

Comparison of the effects of growth hormone (GH), insulin‐like growth factor I (IGF‐I), and insulin on forearm muscle phenylalanine balance (Phe Bal), protein synthesis (Phe Uptake), and protein degradation (Phe Release). Each bar indicates the change in the respective outcome measure caused by each hormone. All three hormones are anabolic (a positive shift in Phe Bal). GH causes net anabolism, however, through increasing protein synthesis. Insulin, in contrast, promotes anabolism by decreasing degradation. IGF‐I exerts both actions, which appear to be dose dependent .

Figure 2. Figure 2.

Integrative view of muscle protein anabolism. Overall, muscle protein anabolism is a balance of the individual effects on protein synthesis and degradation. Whereas insulin acts primarily to suppress protein degradation, growth hormone (GH) stimulates protein synthesis. Testosterone may stimulate synthesis directly or via altering muscle sensitivity to GH. Insulin‐like growth factor‐I (IGF‐I) is synthesized in a paracrine mode in muscle under the regulation of GH, which may in turn act back on muscle to stimulate synthesis and suppress protein degradation.



Figure 1.

Comparison of the effects of growth hormone (GH), insulin‐like growth factor I (IGF‐I), and insulin on forearm muscle phenylalanine balance (Phe Bal), protein synthesis (Phe Uptake), and protein degradation (Phe Release). Each bar indicates the change in the respective outcome measure caused by each hormone. All three hormones are anabolic (a positive shift in Phe Bal). GH causes net anabolism, however, through increasing protein synthesis. Insulin, in contrast, promotes anabolism by decreasing degradation. IGF‐I exerts both actions, which appear to be dose dependent .



Figure 2.

Integrative view of muscle protein anabolism. Overall, muscle protein anabolism is a balance of the individual effects on protein synthesis and degradation. Whereas insulin acts primarily to suppress protein degradation, growth hormone (GH) stimulates protein synthesis. Testosterone may stimulate synthesis directly or via altering muscle sensitivity to GH. Insulin‐like growth factor‐I (IGF‐I) is synthesized in a paracrine mode in muscle under the regulation of GH, which may in turn act back on muscle to stimulate synthesis and suppress protein degradation.

References
 1. Albertsson‐Wikland, K., S. Eden, and O. Isaksson. Analysis of early responses to growth hormone on amino acid transport and protein synthesis in diaphragms of young normal rats. J. Endocrinol. 106: 291–297, 1980.
 2. Albertsson‐Wikland, K., and O. Isaksson. Time course of the effect of growth hormone in vitro on amino acid and monosaccharide transport and on protein synthesis in diaphragm of young normal rats. J. Endocrinol. 102: 1445–1451, 1978.
 3. Argetsinger, L. S., G. S. Campbell, X. Yang, B. A. Witthuhn, O. Silvennoinen, J. N. Ihle, and C. Carter‐Su. Identification of JAK2 as a growth hormone receptor‐associated tyrosine kinase. Cell 74: 237–244, 1993.
 4. Ashford, A. J., and V. M. Pain. Effect of diabetes on the rates of synthesis and degradation of ribosomes in rat muscle and liver in vivo. J. Biol. Chem. 261: 4059–4065, 1986.
 5. Ashford, A. J., and V. M. Pain. Insulin stimulation of growth in diabetic rats—Synthesis and degradation of ribosomes and total tissue protein in skeletal muscle and heart. J. Biol. Chem. 261: 4066–4070, 1986.
 6. Attie, K. M., R. Ramirez‐Nelson, F. A. Conte, S. L. Kaplan, and M. M. Grumbach. The pubertal growth spurt in eight patients with true precocious puberty and growth hormone deficiency: evidence for a direct role of sex steroids. J. Clin. Endocrinol. Metab. 71: 975–983, 1990.
 7. Ayling, C. M., B. H. Moreland, J. M. Zanelli, and D. Schulster. Human growth hormone treatment of hypophysectomized rats increases the proportion of type‐1 fibres in skeletal muscle. J. Endocrinol. 123: 429–435, 1989.
 8. Baillie, A. G. S., and P. J. Garlick. Attenuated responses of muscle protein synthesis to fasting and insulin in adult female rats. Am. J. Physiol. 262 (Endocrinol. Metab. 25): E1–E5, 1992.
 9. Banskota, N. K., R. Taub, K. Zellner, and G. L. King. Insulin, insulin‐like growth factor‐I and platelet derived growth factor interact additively in the induction of the protooncogene c‐myc and cellular proliferation in cultured bovine aortic smooth muscle cells. Mol. Endocrinol. 3: 1183–1190, 1989.
 10. Belcher, H. J. C. R., and H. Ellis. Somatotropin and wound healing after injury. J. Clin. Endocrinol. Metab. 70: 939–943, 1990.
 11. Bennett, W. M., and M. W. Haymond. Growth hormone and lean tissue catabolism during long‐term glucocorticoid treatment. Clin. Endocrinol. 36: 161–164, 1992.
 12. Beshta, S. A., P. S. Sharp, S. V. Gelding, D. Halliday, and D. G. Johnston. Whole body leucine turnover in adults on conventional treatment for hypopituitarism. Acta Endocrinol. (Co‐penh.) 129: 158–164, 1993.
 13. Bhasin, S., T. Storer, N. Berman, C. Callegari, B. Clevenger, J. Phillips, T. J. Bunnell, R. Tricker, A. Shirazi, and R. Casaburi. The effects of supraphysiologic doses of testosterone on muscle size and strength in normal men. N. Engl. J. Med. 335: 1–7, 1996.
 14. Binnerts, A., G. R. Swart, J. H. P. Wilson, N. Hoogerbrugge, H. A. P. Pols, J. C. Birkenhager, and S. W. J. Lamberts. The effect of growth hormone administration in growth hormone deficient adults on bone, protein, corbohydrate, and lipid homeostasis, as well as on body compsition. Clin. Endocrinol. 37: 79–87, 1992.
 15. Blanchard, P., M. Ellis, C. Maltin, G. Falkous, J. B. Harris, and D. Mantle. Effect of growth promoters on pig muscle structural protein and proteolytic enzyme levels in vivo and in vitro. Biochimie 75: 839–847, 1993.
 16. Bornfeldt, K. E., R. A. Gidlof, A. Wasteson, M. Lake, A. Skottner, and H. J. Arnquist. Binding and biological effects of insulin, insulin analogues, and insulin‐like growth factors in rat aortic smooth muscle cells. Comparison of maximal growth promoting activities. Diabetologia 34: 307–313, 1991.
 17. Bornfeldt, K. E., A. Skottner, and H. J. Arnquist. In vivo regulation of messenger RNA encoding insulin‐like growth factor‐I (IGF‐I) and its receptor by diabetes, insulin, and IGF‐I in rat muscle. J. Endocrinol. 135: 203–211, 1992.
 18. Boulware, S. D., W. V. Tamborlane, L. S. Matthews, and R. S. Sherwin. Diverse effects of insulin‐like growth factor I on glucose, lipid, and amino acid metabolism. Am. J. Physiol. 262 (Endocrinol. Metab. 25): E130–E133, 1992.
 19. Cahill Jr, G. F. Starvation in man. N. Engl. J. Med. 282: 668–675, 1970.
 20. Cameron, C. M., J. L. Kostyo, N. A. Adamafio, P. Brostedt, P. Roos, A. Skottner, A. Forsman, L. Fryklund, and B. Skoog. The acute effects of growth hormone on amino acid transport and protein synthesis are due to its insulin‐like action. Endocrinology 122: 471–474, 1988.
 21. Castellino, P., L. Luzi, D. C. Simonson, M. Haymond, and R. A. DeFronzo. Effect of insulin and plasma amino acid concentrations on leucine metabolism in man. J. Clin. Invest. 80: 1784–1793, 1987.
 22. Cheek, D. B. The effect of growth hormone on cell multiplication and cell size. In: Human Pituitary Growth Hormone: The 5th Ross Conference on Pediatric Research, edited by R. M. Blizzard. Columbus, OH: Ross Laboratories, 1966, p. 58–73.
 23. Cheek, D. B., and J. B. Graystone. The action of insulin, growth hormone, and epinephrine on cell growth in liver, muscle, and brain of the hypophysectomized rat. Pediatr. Res. 3: 77–88, 1969.
 24. Cittadini, A., A. Cuocolo, B. Merola, S. Fazio, D. Sabatini, E. Nicolai, A. Colao, S. Longobardi, G. Lombardi, and L. Sacca. Impaired cardiac performance in GH‐deficient adults and its improvement after GH replacement. Am. J. Physiol. 267 (Endocrinol. Metab. 30): E219–E225, 1994.
 25. Clark, R. G., J.‐O. Jansson, O. Isaksson, and I. C. A. F. Robinson. Intravenous growth hormone: growth responses to patterned infusions in hypophysectomized rats. J. Endocrinol. 104: 53–61, 1985.
 26. Clemmons, D. R., A. Smith‐Banks, and L. E. Underwood. Reversal of diet‐induced catabolism by infusion of recombinant insulin‐like growth factor‐I in humans. J. Clin. Endocrinol. Metab. 75: 234–238, 1992.
 27. Collier, R. J., J. L. Vicini, C. D. Knight, C. L. McLaughlin, and C. A. Baile. Impact of somatotropins on nutrient requirements in domestic animals. J. Nutr. 122: 855–860, 1992.
 28. Collipp, P. J., V. Curti, J. Thomas, R. K. Sharma, V. T. Maddaiah, and S. H. Cohn. Body composition changes in children receiving human growth hormone. Metabolism 22: 589–595, 1973.
 29. Copeland, K. C., and K. S. Nair. Acute growth hormone effects on amino acid and lipid metabolism. J. Clin. Endocrinol. Metab. 78: 1040–1047, 1994.
 30. Copeland, K. C., and K. S. Nair. Recombinant human insulinlike growth factor‐I increases forearm blood flow. J. Clin. Endocrinol. Metab. 79: 230–232, 1994.
 31. Coux, O., K. Tanaka, and A. L. Goldberg. Structure and function of the 20S and 26S proteasomes. Annu. Rev. Biochem. 65: 801–826, 1996.
 32. Cuneo, R. C., F. Salomon, C. M. Wiles, R. Hesp, and P. H. Sonksen. Growth hormone treatment in growth hormone‐deficient adults. I. Effects on muscle mass and strength. J. Appl. Physiol. 70: 688–694, 1991.
 33. Cuneo, R. C., F. Salomon, C. M. Wiles, J. M. Round, D. A. Jones, R. Hesp, and P. H. Sonksen. Histology of skeletal muscle in adults with GH deficiency: comparison with normal muscle and response to GH treatment. Horm. Res. 37: 23–28, 1992.
 34. Dahms, W. T., R. P. Owens, S. C. Kalhan, D. S. Kerr, and R. K. Danish. Urea synthesis, nitrogen balance, and glucose turnover in growth hormone‐deficient children before and after growth hormone administration. Metabolism 38: 197–203, 1989.
 35. Dardevet, D., C. Sornet, D. Attaix, V. E. Baracos, and J. Grizard. Insulin‐like growth factor I and insulin resistance in skeletal muscles of adult and old rats. Endocrinology 134: 1475–1484, 1994.
 36. Daughaday, W. H., and P. Rotwein. Insulin‐like growth factors I and II. Peptide messenger ribonucleic acid and gene structures, serum, and tissue concentrations. Endocr. Rev. 10: 68–91, 1989.
 37. Davidson, M. B. Effect of growth hormone on carbohydrate and lipid metabolism. Endocr. Rev. 8: 115–131, 1987.
 38. Dawson‐Hughes, B., D. Stern, J. Goldman, and S. Reichlin. Regulation of growth hormone and somatomedin‐C secretion in postmenopausal women: effect of physiological estrogen replacement. J. Clin. Endocrinol. Metab. 63: 424–432, 1986.
 39. De Vroede, M. A., J. A. Romanus, M. L. Standaert, R. J. Pollet, S. P. Nissley, and M. M. Rechler. Interaction of insulin‐like growth factors with a non‐fusing mouse muscle cell line: binding, action, and receptor down regulation. Endocrinology 114: 1917–1929, 1984.
 40. Denne, S. C., E. A. Liechty, Y. M. Liu, G. Brechtel, and A. D. Baron. Proteolysis in skeletal muscle and whole body in response to euglycemic hyperinsulinemia in normal adults. Am. J. Physiol. 261 (Endocrinol. Metab. 24): E809–E814, 1991.
 41. Dice, J. F. Molecular determinants of protein half‐lives in eukaryotic cells. FASEB J. 1: 349–357, 1987.
 42. DiMartino‐Nardi, J., R. Wu, K. Fishman, and P. Saenger. The effect of long‐acting analog of luteinizing hormone–releasing hormone on growth hormone secretory dynamics in children with precocious puberty. J. Clin. Endocrinol. Metab. 73: 902–906, 1991.
 43. Dodson, M. V., R. E. Allen, and K. L. Hossner. Ovine somatomedin, multiplication‐stimulating activity, and insulin promote skeletal muscle satellite cell proliferation in vitro. Endocrinology 117: 2357–2363, 1985.
 44. Dohm, G. L., C. W. Elton, S. Raju, N. D. Mooney, R. Dimarchi, W. J. Pories, E. G. Flickinger, S. M. Atkinson, and J. F. Caro. IGF‐I stimulated glucose transport in human skeletal muscle and IGF‐I resistance in obesity and NIDDM. Diabetes 39: 1028–1032, 1990.
 45. Douglas, R. G., P. D. Gluckman, K. Ball, B. Breier, and J. H. F. Shaw. The effects of infusion of IGF‐I, IGF‐II, and insulin on glucose and protein metabolism in fasted lambs. J. Clin. Invest. 88: 614–622, 1991.
 46. Douglas, R. G., D. A. Humberstone, A. Haystead, and J. H. F. Shaw. Metabolic effects of recombinant human growth hormone: isotopic studies in the postabsorptive state and during total parenteral nutrition. Br. J. Surg. 77: 785–790, 1990.
 47. Eisemann, J. H., A. C. Hammond, and T. S. Rumsey. Tissue protein synthesis and nucleic acid concentrations in steers treated with somatotropin. Br. J. Nutr. 62: 657–671, 1989.
 48. Ekberg, S., L. Carlsson, B. Carlsson, H. Billig, and J. Jansson. Plasma growth hormone pattern regulates epidermal growth factor (EGF) receptor messenger ribonucleic acid levels and EGF binding in the rat liver. Endocrinology 125: 2158–2166, 1989.
 49. Elahi, D., M. McAloon‐Dyke, N. K. Fukagawa, A. L. Sclater, G. A. Wong, R. P. Shannon, K. L. Minaker, J. M. Miles, A. H. Rubenstein, C. J. Vandepol, H. P. Guler, W. R. Good, J. J. Seaman, and R. R. Wolfe. Effects of recombinant human IGF‐I on glucose and leucine kinetics in man. Am. J. Physiol. 265 (Endocrinol. Metab. 28): E831–E838, 1993.
 50. Evans, H. M., and J. A. Long. The effect of the anterior lobe administered intraperitoneally upon growth, maturity, and oestrus cycles of the rat. Anat. Rec. 21: 62–63, 1921.
 51. Evans, H. M., M. E. Simpson, and C. H. Li. The gigantism produced in normal rats by injection of the pituitary pituitary growth hormone. I. Body growth and organ changes. Growth 12: 15–32, 1948.
 52. Fagan, J. M., L. Waxman, and A. L. Goldberg. Red blood cells contain a pathway for the degradation of oxidant‐damaged hemoglobin that does not require ATP or ubiquitin. J. Biol. Chem. 261: 5705–5713, 1986.
 53. Fagin, J. A., C. T. Roberts, D. LeRoith, and A. T. Brown. Coordinate decrease of tissue insulin‐like growth factor I post‐transcriptional alternative mRNA transcripts in diabetes mellitus. Diabetes 38: 428–434, 1989.
 54. Fagin, J. M., L. Waxman, and A. L. Goldberg. Skeletal muscle and liver contain a soluble ATP+ubiquitin‐dependent proteolytic system. Biochem. J. 243: 335–343, 1987.
 55. Fazio, S., D. Sabatini, B. Capaldo, C. Vigorito, A. Giordano, R. Guida, F. Pardo, B. Biondi, and L. Sacca. A preliminary study of growth hormone in the treatment of dilated cardiomyopathy. N. Engl. J. Med. 334: 809–814, 1996.
 56. Felig, P., O. E. Owen, J. Wahren, and G. F. Cahill, Jr. Amino acid metabolismm during prolonged starvation. J. Clin. Invest. 48: 584–594, 1969.
 57. Felsing, N. E., J. A. Brasel, and D. M. Cooper. Effect of low and high intensity exercise on circulating growth hormone in men. J. Clin. Endocrinol. Metab. 75: 157–162, 1992.
 58. Flaim, K. E., J. B. Li, and L. S. Jefferson. Protein turnover in rat skeletal muscle, effects of hypophysectomy and growth hormone. Am. J. Physiol. 234 (Endocrinol. Metab. Gastrointest. Physiol. 3): E38–E43, 1978.
 59. Flakoll, P. J., M. Kulaylat, M. Frexes‐Steed, H. Hourani, L. L. Brown, J. O. Hill, and N. N. Abumrad. Amino acids augment insulin's suppression of whole body proteolysis. Am. J. Physiol. 257 (Endocrinol. Metab. 20): E839–E847, 1989.
 60. Flier, J. S., P. Usher, and A. C. Moses. Monoclonal antibody to the type I insulin‐like (IGF‐I) receptor blocks IGF‐I receptor‐mediated DNA synthesis: Clarification of the mitogenic mechanisms of IGF‐I and insulin in human skin fibroblasts. Proc. Natl. Acad. Sci. USA 83: 664–668, 1986.
 61. Florini, J. R., and C. B. Breuer. Effects of growth hormone on muscle ribosomes and RNA polymerase. Biochemistry 5: 1870–1876, 1966.
 62. Florini, J. R., D. Z. Ewton, S. L. Falen, and J. J. Van Wyk. Biphasic concentration dependency of stimulation of myoblast differentiation by somatomedins. Am. J. Physiol. 250 (Cell Physiol. 19): C771–C778, 1986.
 63. Florini, J. R., M. L. Nicholson, and N. C. Dulak. Effects of peptide anabolic hormones on growth of myoblasts in culture. J. Endocrinol. 101: 32–41, 1977.
 64. Fong, Y., M. Rosenbaum, K. J. Tracey, G. Raman, D. G. Hesse, D. E. Matthews, R. L. Leibel, J. M. Gertner, D. A. Fishman, and S. F. Lowry. Recombinant growth hormone enhances muscle myosin heavy‐chain mRNA accumulation and amino acid accrual in humans. Proc. Natl. Acad. Sci. USA 86: 3371–3374, 1989.
 65. Forbes, G. B. The effects of anabolic steroids on lean body mass: the dose‐response curve. Metabolism 34: 571–573, 1985.
 66. Forbes, G. B., C. R. Porta, B. E. Herr, and R. C. Griggs. Sequence of changes in body composition induced by testosterone and reversal of changes after drug is stopped. JAMA 267: 397–399, 1992.
 67. Forbes, G. B., and J. C. Reina. Adult lean body mass declines with age: some longitudinal observations. Metabolism 19: 653–663, 1970.
 68. Foster, A. R., D. F. Houlihan, C. Gray, F. Medale, B. Fauconneau, S. J. Kaushik, and P. Y. Le Bail. The effects of ovine growth hormone on protein turnover in rainbow trout. Gen. Comp. Endocrinol. 82: 111–120, 1991.
 69. Frayn, K. N., and P. F. Maycock. Regulation of protein metabolism by a physiological concentration of insulin in mouse soleus and extensor diigitorum longus muscles. Biochem. J. 184: 323–330, 1979.
 70. Friedl, K. E., J. R. Dettori, C. J. Hannan, T. H. Patience, and S. R. Plymate. Comparison of the effects of high dose testosterone and 19‐nortestoserone to a replacement dose of testosterone on strength and body composition in normal men. J. Steroid Biochem. Mol. Biol. 40: 607–612, 1991.
 71. Friend, K. E., M. L. Hartman, S. S. Pezzoli, J. L. Clasey, and M. O. Thorner. Both oral and transdermal estrogen replacement increase GH release in postmenopausal women: a clinical research center study. J. Clin. Endocrinol. Metab. 81: 2250–2256, 1996.
 72. Fryburg, D. A. Insulin‐like growth factor I exerts growth hormone‐and insulin‐like actions on human muscle protein metabolism. Am. J. Physiol. 267 (Endocrinol. Metab. 30): E331–E336, 1994.
 73. Fryburg, D. A. Ng‐monomethyl‐l‐arginine inhibits the blood flow but not the insulin‐like responses of forearm muscle to IGF‐I. Possible role of nitric oxide in muscle protein synthesis. J. Clin. Invest. 97: 1319–1328, 1996.
 74. Fryburg, D. A., and E. J. Barrett. Growth hormone acutely stimulates skeletal muscle but not whole body protein synthesis in humans. Metabolism 42: 1223–1227, 1993.
 75. Fryburg, D. A., R. A. Gelfand, and E. J. Barrett. Growth hormone acutely stimulates muscle protein synthesis in normal humans. Am. J. Physiol. 260 (Endocrinol. Metab. 23): E499–E504, 1991.
 76. Fryburg, D. A., L. A. Jahn, S. A. Hill, D. M. Oliveras, and E. J. Barrett. Insulin and insulin‐like growth factor‐I enhance human skeletal muscle protein anabolism during hyperaminoacidemia by different mechanisms. J. Clin. Invest. 96: 1722–1729, 1995.
 77. Fryburg, D. A., R. J. Louard, K. E. Gerow, R. A. Gelfand, and E. J. Barrett. Growth hormone stimulates skeletal muscle protein synthesis and blunts insulin's antiproteolytic action in humans. Diabetes 41: 42A–429, 1992.
 78. Fukagawa, N. K., K. L. Minaker, J. W. Rowe, M. N. Googman, D. W. Matthews, D. M. Bier, and V. R. Young. Insulin‐mediated reduction of whole body protein breakdown—Dose‐response effects on leucine metabolism in postabsorptive man. J. Clin. Invest. 76: 2306–2311, 1985.
 79. Fukagawa, N. K., K. L. Minaker, V. R. Young, and J. W. Rowe. Insulin dose‐dependent reductions in plasma amino acids in man. Am. J. Physiol. 250 (Endocrinol. Metab. 13): E13–E17, 1986.
 80. Fulks, R. M., J. B. Li, and A. L. Goldberg. Effects of insulin, glucose, and amino acids on protein turnover in rat diaphragm. J. Biol. Chem. 250: 290–298, 1975.
 81. Fuller, S. J., J. R. Mynett, and P. H. Sugden. Stimulation of cardiac protein synthesis by insulin‐like growth factors. Biochem. J. 282: 85–90, 1992.
 82. Furono, K., and A. L. Goldberg. The activation of protein degradation in muscle by Ca or muscle injury does not involve a lysosomal mechanism. Biochem. J. 237: 859–864, 1986.
 83. Furono, K., M. N. Goodman, and A. L. Goldberg. Role of different proteoytic systems in the degradation of muscle proteins during denervation atrophy. J. Biol. Chem. 265: 8550–8557, 1990.
 84. Garlick, P. J., M. Fern, and V. R. Preedy. The effect of insulin infusion and food intake on muscle protein synthesis in post‐absorptive rats. Biochem. J. 210: 669–676, 1983.
 85. Garlick, P. J., and I. Grant. Amino acid infusion increases the sensitivity of muscle protein synthesis in vivo to insulin. Biochem. J. 254: 579–584, 1988.
 86. Gelfand, R. A., and E. J. Barrett. Effect of physiologic hyper‐insulinemia on skeletal muscle protein synthesis and breakdown in man. J. Clin. Invest. 80: 1–6, 1987.
 87. Giacca, A., R. Gupta, S. Efendic, K. Hall, A. Skottner, L. Lickley, and M. Vranic. Differential effects of IGF‐I and insulin on glucoregulation and fat metabolism in depancreatectomized dogs. Diabetes 39: 340–347, 1990.
 88. Cillery, P., A. Leperre, F. X. Maquart, and J. P. Borel. Insulinlike growth factor‐I (IGF‐I) stimulates protein synthesis and collagen gene expression in monolayer and lattice cultures of fibroblasts. J. Cell. Physiol. 152: 389–396, 1992.
 89. Goldberg, A. L., and H. M. Goodman. Relationship between growth hormone and muscular work in determining muscle size. J. Physiol. 200: 655–666, 1969.
 90. Goldstein, S., G. J. Sertich, K. R. Levan, and L. S. Phillips. Nutrition and somatomedin. XIX. Molecular regulation of insulinlike growth factor‐I in streptozotocin diabetic rats. Mol. Endocrinol. 2: 1093–1100, 1988.
 91. Goodman, H. M. Early and late effects of growth hormone on the metabolism of glucose in adipose tissue. Endocrinology 76: 1134–1140, 1965.
 92. Gore, D. C., D. Honeycutt, F. Jahoor, R. R. Wolfe, and D. N. Herndon. Effect of exogenous growth hormone on whole body and isolated limb protein kinetics in burned patients. Arch. Surg. 126: 38–43, 1991.
 93. Greenbaum, A. L. Changes in body composition and respiratory quotient of adult female rats treated with purified growth hormone. Biochemistry 54: 400–407, 1953.
 94. Griggs, R. C., K. William, R. F. Jozefowicz, B. E. Herr, G. Forbes, and D. Halliday. Effect of testosterone on muscle mass and muscle protein synthesis. J. Appl. Physiol. 66: 498–503, 1989.
 95. Guler, H., J. Zapf, and E. R. Froesch. Short‐term metabolic effects of recombinant human insulin‐like growth factor I in healthy adults. N. Engl. J. Med. 317: 137–140, 1987.
 96. Guler, H. P., J. Zapf, E. Scheiwiller, and E. R. Froesch. Recombinant human insulin‐like growth factor I stimulates growth and has distinct effects on organ size in hypophysectomized rats. Proc. Natl. Acad. Sci. USA 85: 4889–4893, 1988.
 97. Guller, S., R. E. Corin, K. Yuan‐Wu, and M. Sonenberg. Up‐regulation of vinculin expression in 3T3 preadipose cells by growth hormone. Endocrinology 129: 527–533, 1991.
 98. Gurland, G., G. Ashcom, B. H. Cochran, and J. Schwartz. Rapid events in growth hormone action. Induction of c‐fos and c‐jun transcription in 3T3–F442A preadipocytes. Endocrinology 127: 3187–3195, 1990.
 99. Hammarquist, F., C. Stromberg, A. von der Decken, E. Vinnars, and J. Wernerman. Biosynthetic human growth hormone preserves both muscle protein synthesis and the decrease in muscle‐free glutamine, and improves whole‐body nitrogen economy after operation. Ann. Surg. 216: 184–191, 1992.
 100. Harper, J. M. M., J. B. Soar, and P. J. Buttery. 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. 112: 87–96, 1987.
 101. Henneman, P. H., A. P. Forbes, M. Moldawer, E. F. Dempsey, and E. L. Carroll. Effects of human growth hormone in man. J. Clin. Invest. 39: 1223–1238, 1960.
 102. Herndon, D. N., R. E. Barrow, K. R. Kunkel, L. Broemeling, and R. L. Rutan. Effects of recombinant human growth hormone on donor‐site healing in severely burned children. Ann. Surg. 212: 424–429, 1990.
 103. Hervey, G. R., I. Hutchinson, A. V. Knibbs, L. Burkinshaw, P. R. M. Jones, N. G. Norgan, and M. J. Levell. Anabolic effects of methanedienone in men undergoing athletic training. Lancet 2: 699–702, 1976.
 104. Hill, D. J., C. J. Crace, A. J. Strain, and R. D. G. Milner. Regulation of amino acid uptake and deoxyribonucleic acid synthesis in isolated human fetal fibroblasts and myoblasts: effect of human placental lactogen, somatomedin C, multiplication‐stimulating activity, and insulin. J. Clin. Endocrinol. Metab. 62: 753–760, 1986.
 105. Hintz, R. L. The prismatic case of Creutzfeldt‐Jakob disease associated with pituitary growth hormone treatment. J. Clin. Endocrinol. Metab. 80: 2298–2301, 1995.
 106. Hirschberg, R., and J. D. Kopple. Evidence that insulin‐like growth factor‐I increases renal plasma flow and glomerular filtration rate in fasted rats. J. Clin Invest 83: 326–330, 1989.
 107. Hizuka, N., K. Takano, K. Shizume, K. Asakawa, M. Miyakawa, I. Tanaka, and R. Horika. Insulin‐like growth factor‐I stimulates growth in normal growing rats. Eur. J. Pharmacol. 125: 143–146, 1986.
 108. Horber, F. F., and M. W. Haymond. Human growth hormone prevents the protein catabolic side effects of prednisone in humans. J. Clin. Invest. 86: 265–272, 1990.
 109. Hudlicka, O. Regulation of muscle blood flow. Clin. Physiol. 5: 201–229, 1985.
 110. Hynes, M. A., J. J. Van Wyk, P. J. Brooks, A. J. D'Ercole, M. Jansen, and P. K. Lund. Growth hormone dependence of somatomedin C/insulin‐like growth factor‐I and insulin‐like growth factor‐II messenger ribonucleic acids. Mol. Endocrinol. 1: 233–242, 1987.
 111. Ikkos, D., R. Luft, and C. A. Gemzell. The effect of human growth hormone in man. Lancet i: 720–721, 1958.
 112. Illig, R., and A. Prader. Effect of testosterone on growth hormone secretion in patients with anorchia and delayed puberty. J. Clin. Endocrinol. Metab. 30: 615–618, 1970.
 113. Isgaard, J., L. Carlsson, O. G. P. Isaksson, and J. O. Jansson. Pulsatile intravenous growth hormone (GH) infusion to hypophysectomized rats increases insulin‐like growth factor I messenger ribonucleic acid in skeletal tissues more effectively than continuous GH infusion. J. Endocrinol. 123: 2605–2610, 1988.
 114. Isgaard, J., A. Nilsson, K. Vikman, and O. G. P. Isaksson. Growth hormone regulates the level of insulin‐like growth factor‐I mRNA in rat skeletal muscle. J. Endocrinol. 120: 107–112, 1989.
 115. Isley, W. L., L. E. Underwood, and D. R. Clemmons. Changes in plasma somatomedin‐C in response to ingestion of diets with variable protein and energy content. JPEN 8: 407–411, 1984.
 116. Jacob, R., E. J. Barrett, G. Plewe, K. D. Fagin, and R. S. Sherwin. Acute effects of insulin‐like growth factor I on glucose and amino acid metabolism in the awake fasted rat. J. Clin. Invest. 83: 1717–1723, 1989.
 117. Jacob, R. J., R. S. Sherwin, L. Bowen, D. Fryburg, K. D. Fagin, W. V. Tamborlane, and G. I. Shulman. Metabolic effects of IGF‐I and insulin in spontaneously diabetic BB/W rats. Am. J. Physiol. 260 (Endocrinol. Metab. 23): E262–E268, 1991.
 118. Jaffa, A. A., D. LeRoith, C. T. J. Roberts, P. F. Rust, and R. K. Mayfield. Insulin‐like growth factor‐I produces renal hyperfiltration by a kinin‐mediated mechanism. Am. J. Physiol. 266 (Renal Fluid Electrolyte Physiol. 35): F102–F107, 1994.
 119. Jeevanadam, M., L. Ramias, R. F. Shamos, and W. R. Schiller. Decreased growth hormone levels in the catabolic phase of severe injury. Surgery 111: 495–502, 1992.
 120. Jefferson, L. S., J. B. Li, and S. R. Rannels. Regulation by insulin of amino acid release and protein turnover in the perfused rat hemicorpus. J. Biol. Chem. 252: 1476–1483, 1977.
 121. Jeffries, M. K., and M. L. Vance. GH and Cortisol secretion in patients with burn injury. J. Burn Care Rehabil. 13: 391–395, 1992.
 122. Jiang, Z., G. He, S. Zhang, X. Wang, N. Yang, Y. Zhu, and D. W. Wilmore. Low dose growth hormone and hypocaloric nutrition attenuate the protein‐catabolic response after major operation. Ann. Surg. 210: 513–525, 1989.
 123. Jorgensen, J. O. L., S. A. Pedersen, L. Thuesen, J. Jorgensen, T. Ingemann‐Hansen, N. E. Skakkebaek, and J. S. Christiansen. Beneficial effects of growth hormone treatment in GH‐deficient adults. Lancet i: 1221–1225, 1989.
 124. Jorgensen, J. O. L., L. Thuesen, J. Muller, P. Ovesen, N. E. Skakkebaek, and J. S. Christiansen. Three years of growth hormone treatment in growth hormone‐deficient adults: near normalization of body composition and physical performance. Eur. J. Endocrinol. 130: 224–228, 1994.
 125. Jorgensen, P. H., and T. T. Andreassen. A dose‐response study of the effects of biosynthetic human growth hormone on formation and strength of granulation tissue. Endocrinology 121: 1637–1641, 1987.
 126. Jyung, R. W., T. A. Mustoc, W. H. Busby, and D. R. Clemmons. Increased wound‐breaking strength induced by insulinlike growth factor I in combination with insulin‐like growth factor binding protein‐1. Surgery 115: 233–239, 1994.
 127. Kaiser, F. E., A. J. Silver, and J. E. Morley. The effect of recombinant human growth hormone on malnourished older individuals. J. Am. Geriatr. Soc. 39: 235–240, 1991.
 128. Kaplowitz, P. B. Glucocorticoids enhance somatomedic‐C binding and stimulation of amino acid uptake in human fibroblasts. J. Clin. Endocrinol. Metab. 64: 563–571, 1987.
 129. Kassem, M., W. Blum, J. Ristelli, L. Mosekilde, and E. F. Eriksen. Growth hormone stimulates proliferation and differentiation of normal human osteoblast‐like cells in vitro. Calcif. Tissue Int. 52: 222–226, 1993.
 130. Keller, S. R., L. Lamphere, B. E. Lavan, M. R. Kuhne, and G. E. Lienhard. Insulin and IGF‐I signaling through the Insulin Receptor Substrate 1. Mol. Reprod. Dev. 35: 346–352, 1993.
 131. Kerrigan, J. R., and A. D. Rogol. The impact of gonadal steroid hormone action on growth hormone secretion during childhood and adolescence. Endocr. Rev. 13: 281–298, 1992.
 132. Kettlehut, I. C., S. S. Wing, and A. L. Goldberg. Endocrine regulation of protein breakdown in skeletal muscle. Diabetes Metab. Rev. 4: 751–772, 1988.
 133. Klindt, J., J. J. Ford, and G. J. MacDonald. Synergism of testosterone propionate with growth hormone in promoting growth of hypophysectomized rats: effect of sexual differentiation. J. Endocrinol. 127: 249–256, 1990.
 134. Knobil, E. The pituitary growth hormone: an adventure in physiology. Physiologist 9: 25–44, 1966.
 135. Kochakian, C. D. Testosterone and testosterone acetate and the protein and energy metabolism of castrate dogs. Endocrinology 21: 750–755, 1937.
 136. Korner, A. Anabolic action of growth hormone. Ann. N.Y. Acad. Sci. 148: 408–418, 1968.
 137. Korner, A. The effect of hypophysectomy of the rat and of treatment with growth hormone on the incorporation in vivo of radioactive amino acids into the proteins of subcellular fractions of the rat liver. Biochem. J. 74: 462–471, 1960.
 138. Kostyo, J. L. Rapid effects of growth hormone on amino acid transport and protein synthesis. Ann. N.Y. Acad. Sci. 148: 389–407, 1968.
 139. Kostyo, J. L. Separation of the effects of growth hormone on muscle amino acid transport and protein synthesis. Endocrinology. 75: 113–119, 1964.
 140. Kostyo, J. L., and E. Knobil. The effect of growth hormone on the in vitro incorporation of leucine‐2–14C into the protein of rat diaphragm. Endocrinology 65: 395–401, 1959.
 141. Kostyo, J. L., and D. F. Nutting. Growth hormone and protein metabolism. In: Handbook of Physiology, edited by R. O. Greep and E. B. Astwood. Washington D.C.: American Physiological Society, 1974, Section 7, Vol. 4, part 2, p. 187–210.
 142. Krentz, A. J., F. T. Koster, D. M. Crist, K. Finn, L. Z. Johnson, P. J. Boyle, and D. S. Schade. Anthropometric, metabolic, and immunological effects of recombinant human growth hormone in AIDS and AIDS‐related complex. J. Acquir. Immune Defic. Syndr. 6: 245–251, 1993.
 143. Krotkiewski, M., J. G. Kral, and J. Karlsson. Effects of castration and testosterone substitution on body composition and muscle metabolism in rats. Acta Physiol. Scand. 109: 233–237, 1980.
 144. Kuhura, T., S. Ikeda, A. Ohneda, and Y. Sasaki. Effects of intravenous infusion of 17 amino acids on the secretion of GH, glucagon, and insulin in sheep. Am. J. Physiol. 260 (Endocrinol. Metab. 23): E21–E26, 1991.
 145. Kupfer, S. R., L. E. Underwood, R. C. Baxter, and D. R. Clemmons. Enhancement of the anabolic effects of growth hormone and insulin‐like growth factor 1 by use of both agents simultaneously. J. Clin. Invest. 91: 391–396, 1993.
 146. Laager, R., R. Ninnis, and U. Keller. Comparison of the effects of recombinant human insulin‐like growth factor‐I and insulin on glucose and leucine kinetics in humans. J. Clin. Invest. 92: 1903–1909, 1993.
 147. Lee, M. O., and N. K. Schaffer. Anterior pituitary growth hormone and the composition of growth. J. Nutr. 7: 337–363, 1934.
 148. Lenk, S. E., D. Bhat, W. Blakeney, and W. A. Dunn. Effects of streptozotocin‐induced diabetes on rough endoplasmic reticulum and lysosomes of rat liver. Am. J. Physiol. 263 (Endocrinol. Metab. 26): E856–E862, 1992.
 149. LeRoith, D., and C. J. Roberts. Insulin‐like growth factor I (IGF‐I): a molecular basis for endocrine versus local action. Mol. Cell. Endocrinol. 77: C57–C61, 1991.
 150. Lieberman, S. A., J. Bukar, S. A. Chen, A. C. Celniker, P. G. Compton, J. Cook, J. Albu, A. J. Perlman, and A. R. Hoffman. Effects of recombinant human insulin‐like growth factor‐I (rhIGF‐I) on total and free IGF‐I concentrations, IGF‐binding proteins, and glycemic response in humans. J. Clin. Endocrinol. Metab. 75: 30–36, 1992.
 151. Lindahl, A., J. Isgaard, and O. G. Isaksson. Growth hormone in vivo potentiates the stimulatory effect of insulin‐like growth factor‐I in vitro on colony formation of epiphyseal chondrocytes isolated from hypophysectomized rats. Endocrinology 121: 1070–1075, 1987.
 152. Link, K., R. M. Blizzard, W. S. Evans, D. L. Kaiser, M. W. Parker, and A. D. Rogol. The effects of androgens on the pulsatile release and the 24‐h mean concentration of GH in peripubertal males. J. Clin. Endocrinol. Metab. 62: 159–164, 1986.
 153. Liu, L., G. R. Merriam, and R. J. Sherins. Chronic sex steroid exposure increases mean plasma growth hormone concentration and pulse amplitude in men with isolated hypogonadatrophic hypogonadism. J. Clin. Endocrinol. Metab. 64: 651–656, 1987.
 154. Long, W. M., B. H. L. Chua, B. L. Munger, and H. E. Morgan. Effects of insulin on cardiac lysosomes and protein degradation. Federation Proc. 43: 1295–1300, 1984.
 155. Louard, R. J., D. A. Fryburg, R. A. Gelfand, and E. J. Barrett. Insulin sensitivity of protein and glucose metabolism in human forearm skeletal muscle. J. Clin. Invest. 90: 2348–2354, 1992.
 156. Lowe, W. L. J., M. Adamo, C. T. J. Roberts, and D. LeRoith. Regulation by fasting of rat insulin‐like growth factor I and its receptor. Effects on gene expression and binding. J. Clin. Invest. 84: 619–626, 1989.
 157. MacRae, J. C., L. A. F. Bruce, F. D. D. Hovell, I. C. Hart, J. Inkster, A. Walker, and T. Atkinson. Influence of protein nutrition on the response of growing lambs to exogenous bovine growth hormone. J. Endocrinol. 130: 53–61, 1991.
 158. Madsen, K., A. M. Makower, U. Friberg, S. Eden, and O. Isaksson. Effect of human growth hormone on proteoglycan synthesis in cultured rat chondrocytes. Acta Endocrinol. (Co‐penb.) 108: 338–342, 1985.
 159. Malhotra, A., E. Poon, W.‐Y. Tse, P. J. Pringle, P. C. Hindmarsh, and C. G. D. Brook. The effects of oxandrolone on the growth hormone and gonadal axes in boys with constitutional delay of growth and puberty. Clin. Endocrinol. 38: 393–398, 1993.
 160. Mauras, N., and B. Beaufrere. Recombinant human insulin‐like growth factor‐I enhances whole body protein anabolism and significantly diminishes the protein catabolic effects of prednisone in humans without a diabetogenic effect. J. Clin. Endocrinol. Metab. 80: 869–874, 1995.
 161. Mauras, N., F. F. Horber, and M. W. Haymond. Low dose recombinant human insulin‐like growth factor‐I fails to affect protein anabolism but inhibits islet cell secretion in humans. J. Clin. Endocrinol. Metab. 75: 1192–1197, 1992.
 162. Mauras, N. M., R. M. Blizzard, K. Link, M. L. Johnson, A. D. Rogol, and J. Veldhuis, D. Augmentation of growth hormone secretion during puberty:evidence for a pulse amplitude‐modulated phenomenon. J. Clin. Endocrinol. Metab. 64: 596–601, 1987.
 163. McNulty, P. H., L. H. Young, and E. J. Barrett. Response of rat heart and skeletal muscle protein in vivo to insulin and amino acid infusion. Am. J. Physiol. 264 (Endocrinol. Metab. 27): E958–E965, 1993.
 164. Medina, R., S. S. Wing, and A. L. Goldberg. Increase in levels of polyubiquitin and proteasome mRNA in skeletal muscle during starvation and denervation atrophy. Biochem. J. 307: 631–637, 1995.
 165. Medina, R., S. S. Wing, A. Haas, and A. L. Goldberg. Activation of the ubiquitin‐ATP‐dependent proteolytic system in skeletal muscle during fasting and denervation atrophy. Biomed. Biochim. Acta 50: 347–356, 1991.
 166. Mehls, O., E. Ritz, E. B. Hunziker, P. Eggli, U. Heinrich, and J. Zapf. Improvement of growth and food utilization by human recombinant growth hormone in uremia. Kidney Int. 33: 45–52, 1988.
 167. Meisler, R. H., and G. Howard. Effects of insulin on gene transcription. Anna. Rev. Physiol. 51: 701–714, 1989.
 168. Merimee, T. J., J. Zapf, and E. R. Froesch. Insulin‐like growth factors in the fed and fasted states. J. Clin. Endocrinol. Metab. 55: 999–1002, 1982.
 169. Meuli, C., and E. R. Froesch. Effects of insulin and of NSILA on the perfused rat heart: glucose uptake, lactate production, and efflux of 3‐O‐methylglucose. Eur. J. Clin. Invest. 5: 93–99, 1975.
 170. Mjaaland, M., K. Unneberg, J. Larsson, L. Nilsson, and A. Revhaug. Growth hormone after abdominal surgery attenuated forearm glutamine, alanine, 3‐methylhistadine and total amino acid efflux in patients receiving total parenteral nutrition. Ann. Surg. 217: 413–422, 1993.
 171. Moller, N., J. O. L. Jorgensen, O. Schmitz, J. Moller, J. S. Christiansen, K. Alberti, and H. Orskov. Effects of a growth hormone pulse on total and forearm substrate fluxes in humans. Am. J. Physiol. 258 (Endocrinol. Metab. 21): E86–E91, 1990.
 172. Monier, S., A. Le Cam, and Y. Le Marchand‐Brustel. Insulin and insulin‐like growth factor‐I. Effects on protein synthesis in isolated muscles from lean and goldthioglucose obese mice. Diabetes 32: 392–397, 1983.
 173. Monier, S., and Y. Le Marchand‐Brustel. Effects of insulin and IGF‐I on RNA synthesis in isolated soleus muscle. Mol. Cell. Endocrinol. 37: 109–114, 1984.
 174. Mortimore, G. E. Mechanisms of cellular protein catabolism. Nutr. Rev. 40: 1–12, 1982.
 175. Mortimore, G. E., and C. E. Mondon. Inhibition by insulin of valine turnover in liver—Evidence for a general control of proteolysis. J. Biol. Chem. 245: 2375–2383, 1970.
 176. Mortimore, G. E., A. R. Poso, and B. R. Lardeux. Mechanism and regulation of protein degradation in liver. Diabetes Metab. Rev. 5: 48–70, 1989.
 177. Mortimore, G. E., and W. F. Ward. Internalization of cytoplasmic protein by hepatic lysosomes in basal and deprivation‐induced proteolytic states. J. Biol. Chem. 256: 7659–7665, 1981.
 178. Mowbray, J., J. A. Davies, D. J. Bates, and C. J. Jones. Growth hormone, cyclic nucleotides and the rapid control of translation in heart muscle. Biochem. J. 152: 583–592, 1975.
 179. Mulligan, K., C. Grunfeld, M. K. Hellerstein, R. A. Neese, and M. Schambelan. Anabolic effects of recombinant human growth hormone in patients with wasting associated with human immunodeficiency virus infection. J. Clin. Endocrinol. Metab. 77: 956–962, 1993.
 180. Nair, K. S., G. C. Ford, and D. Halliday. Effect of intravenous insulin treatment on in vivo whole body leucine kinetics and oxygen consumption in insulin‐deprived type I diabetic patients. Metabolism 36: 491–495, 1987.
 181. Nair, K. S., J. S. Garrow, C. Ford, R. F. Mahler, and D. Halliday. Effect of poor diabetic control and obesity on whole body protein metabolism in man. Diabetologia 25: 400–403, 1983.
 182. Ng, E.‐H., C. S. Rock, D. D. Lazarus, L. Stiaino‐Coico, L. L. Moldawer, and S. F. Lowry. Insulin‐like growth factor‐I preserves host lean tissue mass in cancer cachexia. Am. J. Physiol. 262 (Regulatiory Integrative Comp. Physiol. 32): R426–R431, 1992.
 183. O'Brien, R. M., and D. K. Granner. Regulation of gene expression by insulin. Biochem. J. 278: 609–619, 1991.
 184. Olashaw, N. E., J. J. Van Wyk, and W. J. Pledger. Control of late G0 G1 progression and protein modification by SmC/IGF‐I. Am. J. Physiol. 253 (Cell Physiol. 22): C575–C579, 1987.
 185. Pacy, P., K. Nair, C. Ford, and D. Halliday. Failure of insulin infusion to stimulate fractional muscle protein synthesis in type I diabetic patients, anabolic effect of insulin and decreased proteolysis. Diabetes 38: 618–624, 1989.
 186. Painson, J.‐C., M. O. Thorner, R. J. Krieg, and G. S. Tannenbaum. Short‐term adult exposure to estradiol feminizes the male pattern of spontaneous and growth hormone–releasing factor‐stimulated growth hormone secretion in the rat. Endocrinology. 130: 511–519, 1992.
 187. Pape, G. S., M. Friedman, L. E. Underwood, and D. R. Clemmons. The effect of growth hormone on weight gain and pulmonary function in patients with chronic obstructive lung disease. Chest 99: 1495–1500, 1991.
 188. Pearson, E., H. S. Soroff, J. F. Prudden, and M. S. Schwartz. Studies on growth hormone. V. Effect on the mineral and nitrogen balances of burned patients. Am. J. Med. Sci. 239: 17, 1960.
 189. Pell, J. M., and P. C. Bates. Collagen and non‐collagen protein turnover in skeletal muscle of growth hormone‐treated lambs. J. Endocrinol. 115: R1–R4, 1987.
 190. Pertzelan, A., I. Blum, M. Grunebaum, and Z. Laron. The combined effect of growth hormone and methandrostenolone on the linear growth of patients with multiple pituitary hormone deficiencies. Clin. Endocrinol. 6: 271–276, 1977.
 191. Pessin, J. E., and A. L. Frattali. Molecular dynamics of insulin/IGF‐I receptor transmembrane signaling. Mol. Reprod. Dev. 35: 339–345, 1993.
 192. Poggi, C., Y. Le Marchand‐Brustel, J. Zapf, E. R. Froesch, and P. Freychet. Effects of binding of insulin‐like growth factor‐I (IGF‐I) in the isolated soleus muscle of lean and obese mice: comparison with insulin. Endocrinology 105: 723–730, 1979.
 193. Ponting, G. A., H. C. Ward, D. Halliday, and A. J. W. Sim. Protein and energy metabolism with biosynthetic human growth hormone in patients on full intravenous nutritional support. JPEN 14: 437–441, 1990.
 194. Pozefsky, T., P. Felig, J. D. Tobin, J. S. Soeldner, and G. F. Cahill, Jr. Amino acid balance across tissues of the forearm in postoperative man‐Effects of insulin at two dose levels. J. Clin. Invest. 48: 2273–2282, 1976.
 195. Pozefsky, T., R. G. Tancredi, R. T. Moxley, J. Dupre, and J. D. Tobin. Effects of brief starvation on muscle amino acid metabolism in nonobese man. J. Clin. Invest. 57: 444–449, 1976.
 196. Rabinowitz, D., G. A. Klassen, and K. L. Zierler. Effect of human growth hormone on muscle and adipose tissue metabolism in the forearm of man. J. Clin. Invest. 44: 51–61, 1965.
 197. Rannels, D. E., J. B. Li, H. E. Morgan, and L. S. Jefferson. Evaluation of hormone effects on protein turnover in isolated perfused organs. Methods Enzymol. 37: 238–250, 1975.
 198. Reeds, P. J., K. A. Munday, and M. R. Turner. Action of insulin and growth hormone on protein synthesis in muscle from non‐hypophysectomized rabbits. Biochem. J. 125: 515–520, 1971.
 199. Righetti, P., E. P. Little, and G. Wolf. Reutilization of amino acids in protein synthesis in HeLa cells. J. Biol. Chem. 246: 5724–5732, 1971.
 200. Rilemma, J. A., J. L. Kostyo, and L. P. Gimpel. Inhibition of metabolic effects of growth hormone by various inhibitors of‐cyclic nucleotide phosphodiesterase. Biochim. Biophys. Acta 297: 527–539, 1973.
 201. Roeder, R. A., K. L. Hossner, R. G. Sasser, and J. M. Gunn. Regulation of protein turnover by recombinant human insulin‐like growth factor‐I in L6 myotube cultures. Horm. Metab. Res. 20: 698–700, 1988.
 202. Ross, R., J. Miell, E. Freeman, J. Jones, D. Matthews, M. Preece, and C. Buchanan. Critically ill patients have high basal growth hormone levels with attenuated oscillatory activity associated with low levels of insulin‐like growth factor‐I. Clin. Endocrinol. 35: 47–54, 1991.
 203. Rossetti, L., S. Frontoni, R. Dimarchi, R. A. DeFronzo, and A. Giaccari. Metabolic effects of IGF‐I in diabetic rats. Diabetes 40: 444–448, 1991.
 204. Rudman, D., A. G. Feller, L. Cohn, K. R. Shetty, I. W. Rudman, and M. W. Draper. Effects of human growth hormone on body composition in elderly men. Horm. Res. 36 (Suppl 1): 73–81, 1991.
 205. Rudman, D., A. G. Feller, N. S. Nagraj, G. A. Gergans, P. Y. Lalitha, A. F. Goldberg, R. A. Schlenker, L. Cohn, I. W. Rudman, and D. E. Mattson. Effects of human growth hormone in men over 60 years old. N. Engl. J. Med. 323: 1–6, 1990.
 206. Russell, J. A. Effects of growth hormone on protein and carbohydrate metabolism. Am. J. Clin. Nutr. 5: 404–416, 1957.
 207. Russell‐Jones, D. L., A. M. Umpleby, T. R. Hennessy, S. B. Bowes, F. Shojaee‐Moradie, K. D. Hopkins, N. C. Jackson, J. M. Kelly, R. H. Jones, and P. H. Sonksen. Use of a leucine clamp to demonstrate that IGF‐I actively stimulates protein synthesis in normal humans. Am. J. Physiol. 267 (Endocrinol. Metab. 30): E591–E598, 1994.
 208. Russell‐Jones, D. L., A. J. Wiessberger, S. B. Bowes, J. M. Kelly, M. Thomason, A. M. Umpleby, R. H. Jones, and P. H. Sonksen. The effects of growth hormone on protein metabolism in adult growth hormone‐deficient patients. Clin. Endocrinol. 38: 427–431, 1993.
 209. Rutherford, O. M., D. A. Jones, J. M. Round, and M. A. Preece. Changes in skeletal muscle after discontinuation of growth hormone treatment in young adults with hypopituitarism. Acta Paediatr. Scand. Suppl. 356: 61–63, 1989.
 210. Salmon, W. D., Jr., and M. R. DuVall. In vitro stimulation of leucine incorporation into muscle and cartilage protein by a serum fraction with sulfation activity: differentiation of effects from those of growth hormone and insulin. Endocrinology 87: 1168–1180, 1987.
 211. Salmon, W. D., Jr., and W. Daughaday. A hormonally controlled serum factor which stimulates sulfate incorporation by cartilage in vitro. J. Lab. Clin. Med. 49: 825–836, 1957.
 212. Salomon, F., R. Cuneo, R. Hesp, and P. Sonksen. The effects of treatment with recombinant human growth hormone on body composition and metabolism in adults with growth hormone deficiency. N. Engl. J. Med. 321: 1797–1803, 1989.
 213. Sanford, C. F., E. E. Griffin, and K. Wildenthal. Synthesis and degradation of myocardial protein during the development and regression of thyrozine induced cardiac hypertrophy in rats. Circ. Res. 43: 688–694, 1978.
 214. Sasaoka, T., D. W. Rose, B. H. Jhun, A. R. Saltiel, B. Draznin, and J. M. Olefsky. Evidence for a functional role of Shc proteins in mitogenic signaling induced by insulin, insulin‐like growth factor‐I, and epidermal growth factor. J. Biol. Chem. 269: 13689–13694, 1994.
 215. Scheiwilkr, E., H. P. Guler, J. Merryweather, C. Scandella, W. Maerkl, J. Zapf, and E. R. Foresch. Growth restoration of insulin‐deficient diabetic rats by recombinant human insulin‐like growth factor‐I. Nature. 323: 169–171, 1986.
 216. Schwander, J., C. Hauri, J. Zapf, and E. R. Froesch. Synthesis and secretion of insulin‐like growth factor and its binding protein by the perfused rat liver: dependence on growth hormone status. Endocrinology 113: 297–305, 1983.
 217. Schwartz, J. Rapid modulation of protein synthesis in normal rats by specific neutralization and replacement of growth hormone. Endocrinology 111: 2087–2090, 1982.
 218. Scow, R. O. Effect of growth hormone and thyroxine on growth and chemical composition of muscle, bone and other tissues in thyroidectomized‐hypophysectomized rats. Am. J. Physiol. 196: 859–865, 1959.
 219. Scow, R. O. Effect of growth hormone on various protein fractions in striated muscle of thyroidectomized and hypophysectomized rats. Am. J. Physiol. 173: 199–206, 1953.
 220. Scow, R. O., and S. N. Hagan. Effect of testosterone propionate and growth hormone on growth and chemical composition of muscle and other tissues in hypophysectomized male rats. Endocrinology 77: 852–858, 1965.
 221. Seve, B., O. Ballevre, P. Ganier, J. Noblet, J. Prugnaud, and C. Obled. Recombinant procine somatotropin and dietary protein enhance protein synthesis in growing pigs. J. Nutr. 123: 529–540, 1993.
 222. Sherwin, R. S., G. A. Schulman, R. Hendler, M. Walesky, A. Belous, and W. Tamborlane. Effect of growth hormone on oral glucose tolerance and circulating metabolic fuels in man. Diabetologia 24: 155–161, 1983.
 223. Skottner, A., R. G. Clark, I. C. A. F. Robinson, and L. Fryklund. Recombinant human insulin‐like growth factor: testing the somatomedin hypothesis in hypophysectomized rats. J. Endocrinol. 112: 123–132, 1987.
 224. Snyder, D. K., L. E. Underwood, and D. R. Clemmons. Anabolic effects of growth hormone in obese, diet‐restricted subjects are dose dependent. Am. J. Clin. Nutr. 52: 431–437, 1990.
 225. Soliman, A. T., E. H. I. Hassan, M. K. Aref, R. L. Hintz, R. G. Rosenfeld, and A. D. Rogol. Serum insulin‐like growth factors I and II concentrations and growth hormone and insulin responses to arginine infusion in children with protein energy malnutrition before and after nutritional rehabilitation. Pediatr. Res. 20: 1122–1130, 1986.
 226. Sonntag, W. E., V. W. Hylka, and J. Meites. Growth hormone restores protein synthesis in skeletal muscle of old male rats. J. Gerontol. 40: 689–694, 1985.
 227. Sonntag, W. E., V. W. Hylka, and J. Meites. Impaired ability of old male rats to secrete growth hormone in vivo but not in vitro in response to hpGRF. Endocrinology 113: 2305–2307, 1983.
 228. Sonntag, W. E., R. W. Steger, L. J. Forman, and J. Meites. Decreased pulsatile release of growth hormone in old male rats. Endocrinology 107: 1875–1879, 1980.
 229. Soos, M. A., C. E. Field, and K. Siddle. Purified hybird insulin/insulin‐like growth factor‐I receptors bind insulin‐like growth factor‐I but not insulin, with high affinity. Biochem. J. 290: 419–426, 1993.
 230. Soos, M. A., and K. Siddle. Immunological relationships between receptors for insulin and insulin‐like growth factor‐I. Biochem. J. 263: 553–563, 1989.
 231. Stirewalt, W. S., R. B. Low, and J. M. Slaiby. Insulin sensitivity and responsiveness of epitrochlearis and soleus muscles from fed and starved rats. Biochem. J. 227: 355–362, 1985.
 232. Stracke, H., A. Schulz, D. Moeller, S. Rossol, and H. Schatz. Effect of growth hormone on osteoblasts and demonstration of somatomedin‐C/IGF‐I in bone organ culture. Acta Endocrinol. (Copenh.) 107: 16–24, 1984.
 233. Strock, L. L., H. Singh, A. Abdullah, J. A. Miller, and D. N. Herndon. The effect of insulin‐like growth factor‐I on postburn hypermetabolism. Surgery 108: 161–164, 1990.
 234. Suchner, J., M. M. Rothkopf, G. Stanislaus, D. H. Elwyn, A. Kvetan, and J. Askanazi. Growth hormone and pulmonary disease: metabolic effects in patients receiving parenteral nutrition. Ann. Intern. Med. 150: 1225–1230, 1990.
 235. Sutton, J., and L. Lazarus. Growth hormone in exercise: comparison of physiological and pharmacological stimuli. J. Appl. Physiol. 41: 523–527, 1976.
 236. Taaffe, D. R., I. H. Jin, T. H. Vu, A. R. Hoffman, and R. Marcus. Lack of effect of recombinant human growth hormone (GH) on muscle morphology and GH‐insulin‐like growth factor expression in resistance‐trained elderly men. J. Clin. Endocrinol. Metab. 81: 421–425, 1996.
 237. Taaffe, D. R., L. Pruitt, J. Reim, R. L. Hintz, G. Butterfield, A. R. Hoffman, and R. Marcus. Effect of recombinant human growth hormone on the muscle strength response to resistance exercise in elderly men. J. Clin. Endocrinol. Metab. 79: 1361–1366, 1994.
 238. Tarinenbaum, G., O. Rorstad, and P. Brazeau. Effects of prolonged food deprivation on the ultraradian growth hormone rhythm and immunoreactive somatostatin tissue levels in the rat. Endocrinology 104: 1733–1738, 1979.
 239. Tanner, J. M., R. H. Whitehouse, P. C. R. Hughes, and B. S. Carter. Relative importance of growth hormone and sex steroids for the growth at puberty of trunk length, limb length, and muscle width in growth hormone‐deficient children. J. Pediatr. 89: 1000–1008, 1976.
 240. Tawa, N. E., and A. L. Goldberg. Suppression of muscle protein turnover and amino acid degradation by dietary protein deficiency. Am. J. Physiol. 263 (Endocrinol. Metab. 26): E317–E325, 1992.
 241. Terlecky, S. R., and J. F. Dice. Polypeptide import and degradation by isolated lysosomes. J. Biol. Chem. 268: 23490–23495, 1993.
 242. Tessari, P., G. Biolo, S. Inchiostro, L. Sacca, R. Nosadini, M. T. Boscarato, R. Trevisan, S. V. Kreutzenberg, and A. Tiengo. Effects of insulin on whole body and forearm leucine and KIC metabolism in type 1 diabetes. Am. J. Physiol. 259 (Endocrinol. Metab. 22): E96–E103, 1990.
 243. Tessari, P., R. Nosadini, R. Trevisan, S. V. De Kreutzenberg, S. Inchiostro, E. Duner, G. Biolo, M. C. Marescotti, A. Tiengo, and G. Crepaldi. Defective suppression by insulin of leucine‐carbon appearance and oxidation in type 1, insulin‐dependent diabetes mellitus. J. Clin. Invest. 77: 1797–1804, 1986.
 244. Thompson, J. L., G. E. Butterfiled, R. Marcus, R. L. Hintz, M. Van Loan, L. Ghiron, and A. R. Hoffman. The effects of recombinant human insulin‐like growth factor‐I and growth hormone on body composition in elderly women. J. Clin. Endocrinol. Metab. 80: 1845–1852, 1995.
 245. Thuesen, L., J. S. Christiansen, K. E. Sorensen, J. O. L. Jorgensen, H. O. Orskov, and P. Henningsen. Myocardial contractility following growth hormone administration in man. Dan. Med. Bull. 35: 193–196, 1988.
 246. Tomas, F. M., S. E. Knowles, C. S. Chandler, G. L. Francis, P. C. Owens, and F. J. Ballard. Anabolic effects of insulin like growth factor 1 (IGF‐1) and IGF‐1 variant in normal female rats. J. Endocrinol. 137: 413–421, 1993.
 247. Tomas, F. M., S. E. Knowles, P. C. Owens, C. S. Chandler, G. L. Francis, and F. J. Ballard. Insulin‐like growth factor‐1 and more potent variants restore growth of diabetic rats without inducing all characteristic insulin effects. Biochem. J. 291: 781–786, 1993.
 248. Tomas, F. M., S. E. Knowles, L. C. Read, C. S. Chandler, S. E. Gargosky, and F. J. Ballard. Effects of full‐length and truncated insulin‐like growth factor‐I on nitrogen balance and muscle protein metabolism in nitrogen‐restricted rats. Endocrinology 128: 97–105, 1991.
 249. Tsukahara, H., D. V. Gordienko, B. Tonshoff, M. C. Gelato, and M. S. Goligorsky. Direct demosntration of insulin‐like growth factor‐I‐induced nitric oxide production by endothelial cells. Kidney Int. 45: 598–604, 1994.
 250. Turkalj, I., U. Keller, R. Ninnis, S. Vosmeer, and W. Stauffacher. Effect of increasing doses of recombinant human insulin‐like growth factor I on glucose, lipid and leucine metabolism in man. J. Clin. Endocrinol. Metab. 75: 1186–191, 1992.
 251. Urban, R. J., Y. H. Bodenburg, C. Gilkison, J. Foxworth, A. R. Coggan, R. R. Wolfe, and A. Ferrando. Testosterone administration to elderly men increases skeletal muscle strength and muscle protein synthesis. Am. J. Physiol. 269 (Endocrinol. Metab. 32): E820–E826, 1995.
 252. Vara‐Thorbeck, R., J. A. Guerrero, J. Rosell, E. Ruiz‐Requena, and J. M. Capitan. Exogenous growth hormone: effects on the catabolic response to surgically produced acute stress and on postoperative immune function. World J. Surg. 17: 530–538, 1993.
 253. Veldhuis, J. D. The neuroendocrine regulation and implications of pulsatile GH secretion: gender effects. Endocrinologist 5: 198–213, 1995.
 254. Vlachopapadopoulou, E., J. J. Zachwieja, J. M. Gertner, D. Manzione, D. M. Bier, D. E. Matthews, and A. E. Slonim. Metabolic and clinical response to recombinant human insulin‐like growth factor I in myotonic dystrophy—a clinical research center study. J. Clin. Endocrinol. Metab. 80: 3715–3723, 1995.
 255. Voerman, H. J., R. J. M. Strack van Schijndel, A. B. J. Groeneveld, H. De Boer, J. P. Nauta, E. A. van der Veen, and L. G. Thijs. Effects of recombinant human growth hormone in patients with severe sepsis. Ann. Surg. 216: 648–655, 1992.
 256. Ward, H. C., D. Halliday, and A. J. W. Sim. Protien and energy metabolism with biosynthetic human growth hormone after gastrointestinal surgery. Ann. Surg. 206: 56–61, 1987.
 257. Weissberger, A. J., and K. K. Y. Ho. Activation of the soma‐totrophic axis by testosterone in adult males: evidence for the role of aromatization. J. Clin. Endocrinol. Metab. 76: 1407–1412, 1993.
 258. Wells, J. A. Binding in the growth hormone receptor complex. Proc. Natl. Acad. Sci. USA 93: 1–6, 1996.
 259. Weltman, A., J. Y. Weltman, R. Schurrer, W. S. Evans, J. D. Veldhuis, and A. Rogol. Endurance training amplifies the pulsatile release of growth hormone: effects of training intensity. J. Appl. Physiol. 72: 2188–2196, 1992.
 260. Wildenthal, K., J. R. Wakeland, J. M. Ord, and J. T. Stull. Interference with lysosomal proteolysis fails to reduce cardiac myosin degradation. Biochem. Biophys. Res. Commun. 96: 793–798, 1980.
 261. Williams, I. H., B. H. L. Chua, R. H. Sahms, D. Siehl, and H. E. Morgan. Effects of diabetes on protein turnover in cardiac muscle. Am. J. Physiol. 239 (Endocrinol. Metab. 8): E178–E185, 1980.
 262. Wilmore, D. W., J. A. Moylan, B. F. Bristow, A. D. Mason, and B. A. Pruitt. Anabolic effects of human growth hormone and high caloric feedings following thermal injury. Surg. Gynecol. Obstet. 138: 875–884, 1974.
 263. Wing, S. S., H. L. Chiang, A. L. Goldberg, and J. F. Dice. Proteins containing peptide related to Lys‐Phe‐Glu‐Arg‐Gln are selectively depleted in liver and heart, but not skeletal muscle, of fasted rats. Biochem. J. 275: 165–169, 1991.
 264. Wing, S. S., and A. L. Goldberg. Glucocorticoids activate the ATP‐ubiquitin‐dependent proteolytic system in skeletal muscle during fasting. Am. J. Physiol. 264 (Endocrinol. Metab. 27): E668–E676, 1993.
 265. Wolf, R. F., M. J. Heslin, E. Newman, D. B. Pearlstone, A. Gonnonne, and M. F. Brennan. Growth hormone and insulin combine to improve whole‐body and skeletal muscle protein kinetics. Surgery 112: 284–291, 1992.
 266. Wolthers, T., T. Grofte, J. O. L. Jorgensen, N. Moller, N. Vahl, J. S. Christiansen, and H. Vilstrup. Effects of Growth Hormone (GH) Administration on Functional Hepatic Nitrogen Clearance: Studies in Normal Subjects and GH‐Deficient Patients. J. Clin. Endocrinol. Metab. 78: 1220–1224, 1994.
 267. Woodhall, S. M., B. H. Breier, U. O'Sullivan, and P. D. Gluckman. The effect of the frequency of subcutaneous insulin‐like growth factor‐I administration on weight gain in growth hormone deficient mice. Horm. Metab. Res. 23: 581–584, 1991.
 268. Yahya, Z. A. H., P. C. Bates, and D. J. Millward. Responses to protein deficiency of plasma and tissue insulin‐like growth factor‐I levels and proteoglycan synthesis rates in rat skeletal muscle and bone. J. Endocrinol. 127: 497–503, 1990.
 269. Yang, H., D. S. Schalch, and D. M. Ney. Anabolic effects of insulin‐like growth factor‐I in calorie restricted and ad libitum fed rats. Nutr. Res. 10: 1151–1160, 1990.
 270. Yang, S., X. Xu, P. Bjorntorp, and S. Eden. Additive effects of growth hormone and testosterone on lipolysis in adipocytes of hypophysectomized rats. J. Endocrinol. 147: 147–152, 1995.
 271. Yarasheski, K. E., J. A. Campbell, K. Smith, M. J. Rennie, J. O. Holloszy, and D. M. Bier. Effect of growth hormone and resistance exercise on muscle growth in young men. Am. J. Physiol. 262 (Endocrinol. Metab. 25): E261–E267, 1992.
 272. Yarasheski, K. E., J. J. Zachwieja, T. J. Angelopoulos, and D. M. Bier. Short‐term growth hormone treatment does not increase muscle protein synthesis in experienced weight lifters. J. Appl. Physiol. 74: 3073–3076, 1993.
 273. Young, J. R., S. Mesiano, R. Hintz, D. J. Caddy, M. M. Ralph, C. A. Browne, and G. D. Thorburn. Growth hormone and testosterone can independently stimulate the growth of hypophysectomized prepubertal lambs without any alteration in circulating concentrations of insulin‐like growth factors. J. Endocrinol. 121: 563–570, 1989.
 274. Young, N. R., H. W. G. Baker, G. Liu, and E. Seeman. Body composition and muscle strength in healthy men receiving testosterone enanthate for contraception. J. Clin. Endocrinol. Metab. 77: 1028–1032, 1993.
 275. Yu, K.‐T., and M. P. Czech. The type I insulin‐like growth factor receptor mediates the rapid effects of multiplication‐stimulating activity on membrane transport systems in rat soleus muscle J. Biol. Chem. 259: 3090–3095, 1984.
 276. Zapf, J., E. Schoenle, and E. R. Froesch. Insulin‐like growth factors I and II: some biological actions and receptor binding characteristics of two purified constituents of nonsuppressible insulin‐like activity of human serum. Eur. J. Biochem. 87: 285–296, 1978.
 277. Zapf, J., C. H. Scmid, and E. R. Froesch. Biological and immunological properties of insulin‐like growth factors (IGF) I and II.;. Clin. Endocrinol. Metab. 13: 3–30, 1984.
 278. Zdanowicz, M. M., J. Moyse, M. A. Wingertzahn, M. O'Connor, S. Teichberg, and A. E. Slonim. Effect of insulin‐like growth factor I in murine myotonic dystrophy. Endocrinology 136: 4880–4886, 1995.
 279. Ziegler, T. R., L. S. Young, E. Ferrari‐Balviera, R. H. Demling, and D. W. Wilmore. Use of human growth hormone combined with nutritional support in a critical care unit. JPEN 14: 574–581, 1990.

Contact Editor

Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite

David A. Fryburg, Eugene J. Barrett. The Regulation of Amino Acid and Protein Metabolism by Growth Hormone. Compr Physiol 2011, Supplement 24: Handbook of Physiology, The Endocrine System, Hormonal Control of Growth: 515-536. First published in print 1999. doi: 10.1002/cphy.cp070517