Tumor hypoglycemia: relationship to high molecular weight insulin-like growth factor-II (original) (raw)

Abstract

The mechanism of tumor-associated hypoglycemia was examined in 11 patients with hepatocellular carcinoma, 6 of whom presented with severe hypoglycemia and 5 in whom plasma glucose was persistently normal. Serum insulin levels in the hypoglycemic patients were low. Although total serum insulin-like growth factor II (IGF-II) levels in both groups of tumor patients were lower than normal, tumor tissue from hypoglycemic patients contained levels of IGF-II mRNA that were 10-20-fold higher than those present in normal liver. IGF-II immunoreactivity consisted in all cases of a mixture of both higher molecular weight forms and material having the character of IGF-II itself. The former comprised a greater proportion of total IGF-II, in patients with hypoglycemia. Studies to characterize the interactions of IGF-II with serum proteins showed that (a) the radiolabeled peptide bound to an approximately 40,000-D protein in sera from both hypoglycemic patients and normal subjects, (b) sera from hypoglycemic patients and normal subjects had similar capacity to bind the radiolabeled peptide, and (c) the apparent affinities of serum binding proteins for IGF-II were the same for both hypoglycemic patients and normal subjects. Whereas, acid extracted, tumor-derived IGF-II immunoreactive peptides with low or intermediate molecular weights bound to serum proteins in a manner indistinguishable from that of IGF-II itself, the highest molecular weight IGF-II immunoreactive peptide exhibited negligible ability to compete for radiolabeled ligand binding to serum proteins. The low affinity of serum binding proteins for this component suggests that high molecular weight IGF-II immunoreactivity might circulate free and be available for interaction with cell-surface receptors.

1672

Images in this article

Selected References

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

  1. Bayne M. L., Applebaum J., Chicchi G. G., Hayes N. S., Green B. G., Cascieri M. A. Structural analogs of human insulin-like growth factor I with reduced affinity for serum binding proteins and the type 2 insulin-like growth factor receptor. J Biol Chem. 1988 May 5;263(13):6233–6239. [PubMed] [Google Scholar]
  2. Bell G. I., Karam J. H., Rutter W. J. Polymorphic DNA region adjacent to the 5' end of the human insulin gene. Proc Natl Acad Sci U S A. 1981 Sep;78(9):5759–5763. doi: 10.1073/pnas.78.9.5759. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Bell G. I., Merryweather J. P., Sanchez-Pescador R., Stempien M. M., Priestley L., Scott J., Rall L. B. Sequence of a cDNA clone encoding human preproinsulin-like growth factor II. 1984 Aug 30-Sep 5Nature. 310(5980):775–777. doi: 10.1038/310775a0. [DOI] [PubMed] [Google Scholar]
  4. Chandalia H. B., Boshell B. R. Hypoglycemia associated with extrapancreatic tumors. Report of two cases with studies on its pathogenesis. Arch Intern Med. 1972 Mar;129(3):447–456. doi: 10.1001/archinte.129.3.447. [DOI] [PubMed] [Google Scholar]
  5. Copeland K. C., Underwood L. E., Van Wyk J. J. Induction of immunoreactive somatomedin C human serum by growth hormone: dose-response relationships and effect on chromatographic profiles. J Clin Endocrinol Metab. 1980 Apr;50(4):690–697. doi: 10.1210/jcem-50-4-690. [DOI] [PubMed] [Google Scholar]
  6. Daughaday W. H., Emanuele M. A., Brooks M. H., Barbato A. L., Kapadia M., Rotwein P. Synthesis and secretion of insulin-like growth factor II by a leiomyosarcoma with associated hypoglycemia. N Engl J Med. 1988 Dec 1;319(22):1434–1440. doi: 10.1056/NEJM198812013192202. [DOI] [PubMed] [Google Scholar]
  7. Daughaday W. H. Radioligand assays for insulin-like growth factor II. Methods Enzymol. 1987;146:248–259. doi: 10.1016/s0076-6879(87)46027-8. [DOI] [PubMed] [Google Scholar]
  8. Daughaday W. H., Trivedi B., Kapadia M. Measurement of insulin-like growth factor II by a specific radioreceptor assay in serum of normal individuals, patients with abnormal growth hormone secretion, and patients with tumor-associated hypoglycemia. J Clin Endocrinol Metab. 1981 Aug;53(2):289–294. doi: 10.1210/jcem-53-2-289. [DOI] [PubMed] [Google Scholar]
  9. Daughaday W. H., Ward A. P., Goldberg A. C., Trivedi B., Kapadia M. Characterization of somatomedin binding in human serum by ultracentrifugation and gel filtration. J Clin Endocrinol Metab. 1982 Nov;55(5):916–921. doi: 10.1210/jcem-55-5-916. [DOI] [PubMed] [Google Scholar]
  10. Davenport M. L., Svoboda M. E., Koerber K. L., Van Wyk J. J., Clemmons D. R., Underwood L. E. Serum concentrations of insulin-like growth factor II are not changed by short-term fasting and refeeding. J Clin Endocrinol Metab. 1988 Dec;67(6):1231–1236. doi: 10.1210/jcem-67-6-1231. [DOI] [PubMed] [Google Scholar]
  11. Drop S. L., Valiquette G., Guyda H. J., Corvol M. T., Posner B. I. Partial purification and characterization of a binding protein for insulin-like activity (ILAs) in human amniotic fluid: a possible inhibitor of insulin-like activity. Acta Endocrinol (Copenh) 1979 Mar;90(3):505–518. doi: 10.1530/acta.0.0900505. [DOI] [PubMed] [Google Scholar]
  12. Fukumoto H., Seino S., Imura H., Seino Y., Eddy R. L., Fukushima Y., Byers M. G., Shows T. B., Bell G. I. Sequence, tissue distribution, and chromosomal localization of mRNA encoding a human glucose transporter-like protein. Proc Natl Acad Sci U S A. 1988 Aug;85(15):5434–5438. doi: 10.1073/pnas.85.15.5434. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Garber A. J., Cryer P. E., Santiago J. V., Haymond M. W., Pagliara A. S., Kipnis D. M. The role of adrenergic mechanisms in the substrate and hormonal response to insulin-induced hypoglycemia in man. J Clin Invest. 1976 Jul;58(1):7–15. doi: 10.1172/JCI108460. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Gorden P., Hendricks C. M., Kahn C. R., Megyesi K., Roth J. Hypoglycemia associated with non-islet-cell tumor and insulin-like growth factors. N Engl J Med. 1981 Dec 10;305(24):1452–1455. doi: 10.1056/NEJM198112103052405. [DOI] [PubMed] [Google Scholar]
  15. Gowan L. K., Hampton B., Hill D. J., Schlueter R. J., Perdue J. F. Purification and characterization of a unique high molecular weight form of insulin-like growth factor II. Endocrinology. 1987 Aug;121(2):449–458. doi: 10.1210/endo-121-2-449. [DOI] [PubMed] [Google Scholar]
  16. Hintz R. L., Liu F. Demonstration of specific plasma protein binding sites for somatomedin. J Clin Endocrinol Metab. 1977 Nov;45(5):988–995. doi: 10.1210/jcem-45-5-988. [DOI] [PubMed] [Google Scholar]
  17. Hyodo T., Megyesi K., Kahn C. R., McLean J. P., Friesen H. G. Adrenocortical carcinoma and hypoglycemia: evidence for production of nonsuppressible insulin-like activity by the tumor. J Clin Endocrinol Metab. 1977 Jun;44(6):1175–1184. doi: 10.1210/jcem-44-6-1175. [DOI] [PubMed] [Google Scholar]
  18. Kahn C. R. The riddle of tumour hypoglycaemia revisited. Clin Endocrinol Metab. 1980 Jul;9(2):335–360. doi: 10.1016/s0300-595x(80)80037-5. [DOI] [PubMed] [Google Scholar]
  19. McFadzean A. J., Yeung R. T. Further observations on hypoglycaemia in hepatocellular carcinoma. Am J Med. 1969 Aug;47(2):220–235. doi: 10.1016/0002-9343(69)90148-x. [DOI] [PubMed] [Google Scholar]
  20. Megyesi K., Kahn C. R., Roth J., Gorden P. Circulating NSILA-s in man: Preliminary studies of stimuli in vivo and of binding to plasma components. J Clin Endocrinol Metab. 1975 Sep;41(3):475–484. doi: 10.1210/jcem-41-3-475. [DOI] [PubMed] [Google Scholar]
  21. Megyesi K., Kahn C. R., Roth J., Gorden P. Hypoglycemia in association with extrapancreatic tumors: demonstration of elevated plasma NSILA-s by a new radioreceptor assay. J Clin Endocrinol Metab. 1974 May;38(5):931–934. doi: 10.1210/jcem-38-5-931. [DOI] [PubMed] [Google Scholar]
  22. Meuli C., Zapf J., Froesch E. R. NSILA-carrier protein abolishes the action of nonsuppressible insulin-like activity (NSILA-S) on perfused rat heart. Diabetologia. 1978 Apr;14(4):255–259. doi: 10.1007/BF01219425. [DOI] [PubMed] [Google Scholar]
  23. Moses A. C., Nissley S. P., Short P. A., Rechler M. M., Podskalny J. M. Purification and characterization of multiplication-stimulating activity. Insulin-like growth factors purified from rat-liver-cell-conditioned medium. Eur J Biochem. 1980 Jan;103(2):387–400. doi: 10.1111/j.1432-1033.1980.tb04325.x. [DOI] [PubMed] [Google Scholar]
  24. Phillips L. S., Vassilopoulou-Sellin R. Nutritional regulation of somatomedin. Am J Clin Nutr. 1979 May;32(5):1082–1096. doi: 10.1093/ajcn/32.5.1082. [DOI] [PubMed] [Google Scholar]
  25. Searle G. L. The use of isotope turnover techniques in the study of carbohydrate metabolism in man. Clin Endocrinol Metab. 1976 Nov;5(3):783–804. doi: 10.1016/s0300-595x(76)80051-5. [DOI] [PubMed] [Google Scholar]
  26. Shoelson S., Haneda M., Blix P., Nanjo A., Sanke T., Inouye K., Steiner D., Rubenstein A., Tager H. Three mutant insulins in man. Nature. 1983 Apr 7;302(5908):540–543. doi: 10.1038/302540a0. [DOI] [PubMed] [Google Scholar]
  27. Tanaka H., Asami O., Hayano T., Sasaki I., Yoshitake Y., Nishikawa K. Identification of a family of insulin-like growth factor II secreted by cultured rat epithelial-like cell line 18,54-SF: application of a monoclonal antibody. Endocrinology. 1989 Feb;124(2):870–877. doi: 10.1210/endo-124-2-870. [DOI] [PubMed] [Google Scholar]
  28. Ullrich A., Shine J., Chirgwin J., Pictet R., Tischer E., Rutter W. J., Goodman H. M. Rat insulin genes: construction of plasmids containing the coding sequences. Science. 1977 Jun 17;196(4296):1313–1319. doi: 10.1126/science.325648. [DOI] [PubMed] [Google Scholar]
  29. Unger R. H. The riddle of tumor hypoglycemia. Am J Med. 1966 Mar;40(3):325–330. doi: 10.1016/0002-9343(66)90127-6. [DOI] [PubMed] [Google Scholar]
  30. Widmer U., Zapf J., Froesch E. R. Is extrapancreatic tumor hypoglycemia associated with elevated levels of insulin-like growth factor II? J Clin Endocrinol Metab. 1982 Nov;55(5):833–839. doi: 10.1210/jcem-55-5-833. [DOI] [PubMed] [Google Scholar]
  31. Zapf J., Hauri C., Waldvogel M., Froesch E. R. Acute metabolic effects and half-lives of intravenously administered insulinlike growth factors I and II in normal and hypophysectomized rats. J Clin Invest. 1986 Jun;77(6):1768–1775. doi: 10.1172/JCI112500. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Zapf J., Schoenle E., Jagars G., Sand I., Grunwald J., Froesch E. R. Inhibition of the action of nonsuppressible insulin-like activity on isolated rat fat cells by binding to its carrier protein. J Clin Invest. 1979 May;63(5):1077–1084. doi: 10.1172/JCI109377. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Zapf J., Waldvogel M., Froesch E. R. Binding of nonsuppressible insulinlike activity to human serum. Evidence for a carrier protein. Arch Biochem Biophys. 1975 Jun;168(2):638–645. doi: 10.1016/0003-9861(75)90296-9. [DOI] [PubMed] [Google Scholar]
  34. 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]
  35. Zumstein P. P., Lüthi C., Humbel R. E. Amino acid sequence of a variant pro-form of insulin-like growth factor II. Proc Natl Acad Sci U S A. 1985 May;82(10):3169–3172. doi: 10.1073/pnas.82.10.3169. [DOI] [PMC free article] [PubMed] [Google Scholar]