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Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1989 Sep;86(17):6778–6782. doi: 10.1073/pnas.86.17.6778

Significance of abnormal serum binding of insulin-like growth factor II in the development of hypoglycemia in patients with non-islet-cell tumors.

W H Daughaday 1, M Kapadia 1
PMCID: PMC297929  PMID: 2771956

Abstract

We reported that serum and tumor from a hypoglycemic patient with a fibrosarcoma contained insulin-like growth factor II (IGF-II), mostly in a large molecular form designated "big IGF-II." We now describe two additional patients with non-islet-cell tumor with hypoglycemia (NICTH) whose sera contained big IGF-II. Removal of the tumor eliminated most of the big IGF-II from the sera of two patients. Because specific IGF-binding proteins modify the bioactivity of IGFs, the sizes of the endogenous IGF-binding protein complexes were determined after neutral gel filtration through Saphadex G-200. Normally about 75% of IGFs are carried as a ternary complex of 150 kDa consisting of IGF, a growth hormone (GH)-dependent IGF-binding protein, and an acid-labile complexing component. The three patients with NICTH completely lacked the 150-kDa complex. IGF-II was present as a 60-kDa complex with variable contributions of smaller complexes. In the immediate postoperative period, a 110-kDa complex appeared rather than the expected 150-kDa complex. Abnormal IGF-II binding may be important in NICTH because the 150-kDa complexes cross the capillary membrane poorly. The smaller complexes present in our patients' sera would be expected to enter interstitial fluid readily, and a 4- to 5-fold increase in the fraction of IGFs reaching the target cells would result.

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Selected References

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  1. AUGUST J. T., HIATT H. H. Severe hypoglycemia secondary to a nonpancreatic fibrosarcoma with insulin activity. N Engl J Med. 1958 Jan 2;258(1):17–20. doi: 10.1056/NEJM195801022580104. [DOI] [PubMed] [Google Scholar]
  2. Baxter R. C. Characterization of the acid-labile subunit of the growth hormone-dependent insulin-like growth factor binding protein complex. J Clin Endocrinol Metab. 1988 Aug;67(2):265–272. doi: 10.1210/jcem-67-2-265. [DOI] [PubMed] [Google Scholar]
  3. Baxter R. C., Martin J. L. Radioimmunoassay of growth hormone-dependent insulinlike growth factor binding protein in human plasma. J Clin Invest. 1986 Dec;78(6):1504–1512. doi: 10.1172/JCI112742. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Binoux M., Hossenlopp P. Insulin-like growth factor (IGF) and IGF-binding proteins: comparison of human serum and lymph. J Clin Endocrinol Metab. 1988 Sep;67(3):509–514. doi: 10.1210/jcem-67-3-509. [DOI] [PubMed] [Google Scholar]
  5. 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]
  6. Daughaday W. H., Mariz I. K., Blethen S. L. Inhibition of access of bound somatomedin to membrane receptor and immunobinding sites: a comparison of radioreceptor and radioimmunoassay of somatomedin in native and acid-ethanol-extracted serum. J Clin Endocrinol Metab. 1980 Oct;51(4):781–788. doi: 10.1210/jcem-51-4-781. [DOI] [PubMed] [Google Scholar]
  7. 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]
  8. Goldberg A. C., Trivedi B., Delmez J. A., Harter H. R., Daughaday W. H. Uremia reduces serum insulin-like growth factor I, increases insulin-like growth factor II, and modifies their serum protein binding. J Clin Endocrinol Metab. 1982 Dec;55(6):1040–1045. doi: 10.1210/jcem-55-6-1040. [DOI] [PubMed] [Google Scholar]
  9. Hardouin S., Hossenlopp P., Segovia B., Seurin D., Portolan G., Lassarre C., Binoux M. Heterogeneity of insulin-like growth factor binding proteins and relationships between structure and affinity. 1. Circulating forms in man. Eur J Biochem. 1987 Dec 30;170(1-2):121–132. doi: 10.1111/j.1432-1033.1987.tb13676.x. [DOI] [PubMed] [Google Scholar]
  10. Haselbacher G. K., Irminger J. C., Zapf J., Ziegler W. H., Humbel R. E. Insulin-like growth factor II in human adrenal pheochromocytomas and Wilms tumors: expression at the mRNA and protein level. Proc Natl Acad Sci U S A. 1987 Feb;84(4):1104–1106. doi: 10.1073/pnas.84.4.1104. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Höppener J. W., Mosselman S., Roholl P. J., Lambrechts C., Slebos R. J., de Pagter-Holthuizen P., Lips C. J., Jansz H. S., Sussenbach J. S. Expression of insulin-like growth factor-I and -II genes in human smooth muscle tumours. EMBO J. 1988 May;7(5):1379–1385. doi: 10.1002/j.1460-2075.1988.tb02954.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. MILLER D. R., BOLINGER R. E., JANIGAN D., CROCKETT J. E., FRIESEN S. R. Hypoglycemia due to nonpancreatic mesodermal tumors: report of two cases. Ann Surg. 1959 Oct;150:684–696. doi: 10.1097/00000658-195910000-00012. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Martin J. L., Baxter R. C. Insulin-like growth factor-binding protein from human plasma. Purification and characterization. J Biol Chem. 1986 Jul 5;261(19):8754–8760. [PubMed] [Google Scholar]
  14. 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]
  15. 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]
  16. Póvoa G., Enberg G., Jörnvall H., Hall K. Isolation and characterization of a somatomedin-binding protein from mid-term human amniotic fluid. Eur J Biochem. 1984 Oct 15;144(2):199–204. doi: 10.1111/j.1432-1033.1984.tb08449.x. [DOI] [PubMed] [Google Scholar]
  17. Reeve A. E., Eccles M. R., Wilkins R. J., Bell G. I., Millow L. J. Expression of insulin-like growth factor-II transcripts in Wilms' tumour. Nature. 1985 Sep 19;317(6034):258–260. doi: 10.1038/317258a0. [DOI] [PubMed] [Google Scholar]
  18. Ron D., Powers A. C., Pandian M. R., Godine J. E., Axelrod L. Increased insulin-like growth factor II production and consequent suppression of growth hormone secretion: a dual mechanism for tumor-induced hypoglycemia. J Clin Endocrinol Metab. 1989 Apr;68(4):701–706. doi: 10.1210/jcem-68-4-701. [DOI] [PubMed] [Google Scholar]
  19. Scott J., Cowell J., Robertson M. E., Priestley L. M., Wadey R., Hopkins B., Pritchard J., Bell G. I., Rall L. B., Graham C. F. Insulin-like growth factor-II gene expression in Wilms' tumour and embryonic tissues. Nature. 1985 Sep 19;317(6034):260–262. doi: 10.1038/317260a0. [DOI] [PubMed] [Google Scholar]
  20. Scott M. G., Cuca G. C., Petersen J. R., Lyle L. R., Burleigh B. D., Daughaday W. H. Specific immunoradiometric assay of insulin-like growth factor I with use of monoclonal antibodies. Clin Chem. 1987 Nov;33(11):2019–2023. [PubMed] [Google Scholar]
  21. 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]
  22. Tricoli J. V., Rall L. B., Karakousis C. P., Herrera L., Petrelli N. J., Bell G. I., Shows T. B. Enhanced levels of insulin-like growth factor messenger RNA in human colon carcinomas and liposarcomas. Cancer Res. 1986 Dec;46(12 Pt 1):6169–6173. [PubMed] [Google Scholar]
  23. 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]
  24. Yeoh S. I., Baxter R. C. Metabolic regulation of the growth hormone independent insulin-like growth factor binding protein in human plasma. Acta Endocrinol (Copenh) 1988 Dec;119(4):465–473. doi: 10.1530/acta.0.1190465. [DOI] [PubMed] [Google Scholar]

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