Skip to main content
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1993 Oct;92(4):1903–1909. doi: 10.1172/JCI116783

Comparison of the effects of recombinant human insulin-like growth factor-I and insulin on glucose and leucine kinetics in humans.

R Laager 1, R Ninnis 1, U Keller 1
PMCID: PMC288356  PMID: 8408642

Abstract

To compare the metabolic effects of elevated plasma concentrations of IGF-I and insulin, overnight-fasted normal subjects were studied twice, once receiving IGF-I and once insulin at doses that resulted in identical increases in glucose uptake during 8-h euglycemic clamping. Recombinant human IGF-I or insulin were infused in one group at high doses (30 micrograms/kg per h IGF-I or 0.23 nmol/kg per h insulin) and in another group at low doses (5 micrograms/kg per h IGF-I or 0.04 nmol/kg per h insulin). Glucose rate of disappearance (measured by [6,6-D2]-glucose infusions) increased from baseline by 239 +/- 16% during high dose IGF-I vs 197 +/- 18% during insulin (P = 0.021 vs IGF-I). Hepatic glucose production decreased by 37 +/- 6% during high dose IGF-I vs 89 +/- 13% during insulin (P = 0.0028 vs IGF-I). IGF-I suppressed whole body leucine flux ([1-13C]-leucine infusion technique) more than insulin (42 +/- 4 vs 32 +/- 3% during high doses, P = 0.0082). Leucine oxidation rate decreased during high dose IGF-I more than during insulin (55 +/- 4 vs 32 +/- 6%, P = 0.0001). The decreases of plasma concentrations of free fatty acids, acetoacetate, and beta-hydroxybutyrate after 8 h of IGF-I and insulin administration were similar. Plasma C-peptide levels decreased by 57 +/- 4% during high doses of IGF-I vs 36 +/- 6% during insulin (P = 0.005 vs IGF-I). The present data demonstrate that, compared to insulin, an acute increase in plasma IGF-I levels results in preferential enhancement of peripheral glucose utilization, diminished suppression of hepatic glucose production, augmented decrease of whole body protein breakdown (leucine flux), and of irreversible leucine catabolism but in similar antilipolytic effects. The data suggest that insulin-like effects of IGF-I in humans are mediated in part via IGF-I receptors and in part via insulin receptors.

Full text

PDF
1903

Selected References

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

  1. Allsop J. R., Wolfe R. R., Burke J. F. Tracer priming the bicarbonate pool. J Appl Physiol Respir Environ Exerc Physiol. 1978 Jul;45(1):137–139. doi: 10.1152/jappl.1978.45.1.137. [DOI] [PubMed] [Google Scholar]
  2. Barkan A. L., Beitins I. Z., Kelch R. P. Plasma insulin-like growth factor-I/somatomedin-C in acromegaly: correlation with the degree of growth hormone hypersecretion. J Clin Endocrinol Metab. 1988 Jul;67(1):69–73. doi: 10.1210/jcem-67-1-69. [DOI] [PubMed] [Google Scholar]
  3. Beaufrere B., Horber F. F., Schwenk W. F., Marsh H. M., Matthews D., Gerich J. E., Haymond M. W. Glucocorticosteroids increase leucine oxidation and impair leucine balance in humans. Am J Physiol. 1989 Nov;257(5 Pt 1):E712–E721. doi: 10.1152/ajpendo.1989.257.5.E712. [DOI] [PubMed] [Google Scholar]
  4. Beaufrère B., Chassard D., Broussolle C., Riou J. P., Beylot M. Effects of D-beta-hydroxybutyrate and long- and medium-chain triglycerides on leucine metabolism in humans. Am J Physiol. 1992 Mar;262(3 Pt 1):E268–E274. doi: 10.1152/ajpendo.1992.262.3.E268. [DOI] [PubMed] [Google Scholar]
  5. Bolinder J., Lindblad A., Engfeldt P., Arner P. Studies of acute effects of insulin-like growth factors I and II in human fat cells. J Clin Endocrinol Metab. 1987 Oct;65(4):732–737. doi: 10.1210/jcem-65-4-732. [DOI] [PubMed] [Google Scholar]
  6. Caro J. F., Poulos J., Ittoop O., Pories W. J., Flickinger E. G., Sinha M. K. Insulin-like growth factor I binding in hepatocytes from human liver, human hepatoma, and normal, regenerating, and fetal rat liver. J Clin Invest. 1988 Apr;81(4):976–981. doi: 10.1172/JCI113451. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Cherrington A. D., Chiasson J. L., Liljenquist J. E., Jennings A. S., Keller U., Lacy W. W. The role of insulin and glucagon in the regulation of basal glucose production in the postabsorptive dog. J Clin Invest. 1976 Dec;58(6):1407–1418. doi: 10.1172/JCI108596. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Czech M. P. Structural and functional homologies in the receptors for insulin and the insulin-like growth factors. Cell. 1982 Nov;31(1):8–10. doi: 10.1016/0092-8674(82)90399-3. [DOI] [PubMed] [Google Scholar]
  9. DeFronzo R. A., Gunnarsson R., Björkman O., Olsson M., Wahren J. Effects of insulin on peripheral and splanchnic glucose metabolism in noninsulin-dependent (type II) diabetes mellitus. J Clin Invest. 1985 Jul;76(1):149–155. doi: 10.1172/JCI111938. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. DeFronzo R. A., Tobin J. D., Andres R. Glucose clamp technique: a method for quantifying insulin secretion and resistance. Am J Physiol. 1979 Sep;237(3):E214–E223. doi: 10.1152/ajpendo.1979.237.3.E214. [DOI] [PubMed] [Google Scholar]
  11. 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]
  12. Froesch E. R., Zapf J. Insulin-like growth factors and insulin: comparative aspects. Diabetologia. 1985 Aug;28(8):485–493. doi: 10.1007/BF00281982. [DOI] [PubMed] [Google Scholar]
  13. 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]
  14. Giacca A., Gupta R., Efendic S., Hall K., Skottner A., Lickley L., Vranic M. Differential effects of IGF-I and insulin on glucoregulation and fat metabolism in depancreatized dogs. Diabetes. 1990 Mar;39(3):340–347. doi: 10.2337/diab.39.3.340. [DOI] [PubMed] [Google Scholar]
  15. Guler H. P., Schmid C., Zapf J., Froesch E. R. Effects of recombinant insulin-like growth factor I on insulin secretion and renal function in normal human subjects. Proc Natl Acad Sci U S A. 1989 Apr;86(8):2868–2872. doi: 10.1073/pnas.86.8.2868. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Guler H. P., Zapf J., Froesch E. R. Short-term metabolic effects of recombinant human insulin-like growth factor I in healthy adults. N Engl J Med. 1987 Jul 16;317(3):137–140. doi: 10.1056/NEJM198707163170303. [DOI] [PubMed] [Google Scholar]
  17. Guler H. P., Zapf J., Schmid C., Froesch E. R. Insulin-like growth factors I and II in healthy man. Estimations of half-lives and production rates. Acta Endocrinol (Copenh) 1989 Dec;121(6):753–758. doi: 10.1530/acta.0.1210753. [DOI] [PubMed] [Google Scholar]
  18. Hardouin S., Gourmelen M., Noguiez P., Seurin D., Roghani M., Le Bouc Y., Povoa G., Merimee T. J., Hossenlopp P., Binoux M. Molecular forms of serum insulin-like growth factor (IGF)-binding proteins in man: relationships with growth hormone and IGFs and physiological significance. J Clin Endocrinol Metab. 1989 Dec;69(6):1291–1301. doi: 10.1210/jcem-69-6-1291. [DOI] [PubMed] [Google Scholar]
  19. Herbert V., Lau K. S., Gottlieb C. W., Bleicher S. J. Coated charcoal immunoassay of insulin. J Clin Endocrinol Metab. 1965 Oct;25(10):1375–1384. doi: 10.1210/jcem-25-10-1375. [DOI] [PubMed] [Google Scholar]
  20. Holst J. J., Aasted B. Production and evaluation of glucagon antibodies for radioimmunoassay. Acta Endocrinol (Copenh) 1974 Dec;77(4):715–726. doi: 10.1530/acta.0.0770715. [DOI] [PubMed] [Google Scholar]
  21. Horber F. F., Horber-Feyder C. M., Krayer S., Schwenk W. F., Haymond M. W. Plasma reciprocal pool specific activity predicts that of intracellular free leucine for protein synthesis. Am J Physiol. 1989 Sep;257(3 Pt 1):E385–E399. doi: 10.1152/ajpendo.1989.257.3.E385. [DOI] [PubMed] [Google Scholar]
  22. Jacob R. J., Sherwin R. S., Bowen L., Fryburg D., Fagin K. D., Tamborlane W. V., Shulman G. I. Metabolic effects of IGF-I and insulin in spontaneously diabetic BB/w rats. Am J Physiol. 1991 Feb;260(2 Pt 1):E262–E268. doi: 10.1152/ajpendo.1991.260.2.E262. [DOI] [PubMed] [Google Scholar]
  23. Jacob R., Barrett E., Plewe G., Fagin K. D., Sherwin R. S. Acute effects of insulin-like growth factor I on glucose and amino acid metabolism in the awake fasted rat. Comparison with insulin. J Clin Invest. 1989 May;83(5):1717–1723. doi: 10.1172/JCI114072. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Küry D., Keller U. Trimethylsilyl-O-methyloxime derivatives for the measurement of [6,6-2H2]-D-glucose-enriched plasma samples by gas chromatography-mass spectrometry. J Chromatogr. 1991 Dec 6;572(1-2):302–306. doi: 10.1016/0378-4347(91)80494-w. [DOI] [PubMed] [Google Scholar]
  25. Livingston N., Pollare T., Lithell H., Arner P. Characterisation of insulin-like growth factor I receptor in skeletal muscles of normal and insulin resistant subjects. Diabetologia. 1988 Dec;31(12):871–877. doi: 10.1007/BF00265369. [DOI] [PubMed] [Google Scholar]
  26. McGuire E. A., Helderman J. H., Tobin J. D., Andres R., Berman M. Effects of arterial versus venous sampling on analysis of glucose kinetics in man. J Appl Physiol. 1976 Oct;41(4):565–573. doi: 10.1152/jappl.1976.41.4.565. [DOI] [PubMed] [Google Scholar]
  27. Miles J., Glasscock R., Aikens J., Gerich J., Haymond M. A microfluorometric method for the determination of free fatty acids in plasma. J Lipid Res. 1983 Jan;24(1):96–99. [PubMed] [Google Scholar]
  28. Molina J. M., Baron A. D., Edelman S. V., Brechtel G., Wallace P., Olefsky J. M. Use of a variable tracer infusion method to determine glucose turnover in humans. Am J Physiol. 1990 Jan;258(1 Pt 1):E16–E23. doi: 10.1152/ajpendo.1990.258.1.E16. [DOI] [PubMed] [Google Scholar]
  29. Rizza R. A., Mandarino L. J., Gerich J. E. Dose-response characteristics for effects of insulin on production and utilization of glucose in man. Am J Physiol. 1981 Jun;240(6):E630–E639. doi: 10.1152/ajpendo.1981.240.6.E630. [DOI] [PubMed] [Google Scholar]
  30. 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]
  31. Schwenk W. F., Berg P. J., Beaufrere B., Miles J. M., Haymond M. W. Use of t-butyldimethylsilylation in the gas chromatographic/mass spectrometric analysis of physiologic compounds found in plasma using electron-impact ionization. Anal Biochem. 1984 Aug 15;141(1):101–109. doi: 10.1016/0003-2697(84)90431-7. [DOI] [PubMed] [Google Scholar]
  32. Schwenk W. F., Tsalikian E., Beaufrere B., Haymond M. W. Recycling of an amino acid label with prolonged isotope infusion: implications for kinetic studies. Am J Physiol. 1985 Apr;248(4 Pt 1):E482–E487. doi: 10.1152/ajpendo.1985.248.4.E482. [DOI] [PubMed] [Google Scholar]
  33. 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]
  34. Zapf J., Schmid C., Guler H. P., Waldvogel M., Hauri C., Futo E., Hossenlopp P., Binoux M., Froesch E. R. Regulation of binding proteins for insulin-like growth factors (IGF) in humans. Increased expression of IGF binding protein 2 during IGF I treatment of healthy adults and in patients with extrapancreatic tumor hypoglycemia. J Clin Invest. 1990 Sep;86(3):952–961. doi: 10.1172/JCI114797. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Zapf J., Walter H., Froesch E. R. Radioimmunological determination of insulinlike growth factors I and II in normal subjects and in patients with growth disorders and extrapancreatic tumor hypoglycemia. J Clin Invest. 1981 Nov;68(5):1321–1330. doi: 10.1172/JCI110379. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Zenobi P. D., Graf S., Ursprung H., Froesch E. R. Effects of insulin-like growth factor-I on glucose tolerance, insulin levels, and insulin secretion. J Clin Invest. 1992 Jun;89(6):1908–1913. doi: 10.1172/JCI115796. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Zorzano A., James D. E., Ruderman N. B., Pilch P. F. Insulin-like growth factor I binding and receptor kinase in red and white muscle. FEBS Lett. 1988 Jul 18;234(2):257–262. doi: 10.1016/0014-5793(88)80093-0. [DOI] [PubMed] [Google Scholar]
  38. van Stekelenburg G. J., de Bruyn J. W. A simple gas chromatographic determination of acetone and beta-ketobutyric acid in blood serum by means of head space gas sampling. Clin Chim Acta. 1970 May;28(2):233–237. doi: 10.1016/0009-8981(70)90085-9. [DOI] [PubMed] [Google Scholar]

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

RESOURCES