Skip to main content
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1988 Jun;81(6):1971–1978. doi: 10.1172/JCI113545

Nonbinding inhibitory antiinsulin receptor antibodies. A new type of autoantibodies in human diabetes.

G Boden 1, Y Fujita-Yamaguchi 1, R Shimoyama 1, J J Shelmet 1, L Tappy 1, I Rezvani 1, O E Owen 1
PMCID: PMC442650  PMID: 2968369

Abstract

Sera and their IgG from 10/104 diabetic patients (five with insulin-dependent and five with noninsulin-dependent diabetes, NIDDM), contained antibodies that bound 125I-labeled purified human insulin receptors. 9 of these 10 sera failed to inhibit insulin binding (to rat hepatocytes and human placental membranes), did not stimulate glucose oxidation (by isolated rat adipocytes), and did not bind human placental IGF-1 receptors. Only one serum (and its IgG) modestly inhibited insulin binding and stimulated glucose oxidation. We conclude (a) that sera from 9/104 diabetics (five insulin-dependent and four noninsulin-dependent) contained a newly identified species of IgG antiinsulin receptor autoantibodies (AIRA), which bound to the insulin receptor at a locus different from the insulin binding site and did not inhibit insulin binding; and (b) that only 1/104 diabetic sera contained low-titer "conventional" antiinsulin receptor autoantibodies that bound to the insulin receptor at or near the insulin binding site, inhibited insulin binding and caused a clinical condition, which was difficult to distinguish from typical NIDDM.

Full text

PDF
1971

Images in this article

Selected References

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

  1. Boden G., Shimoyama R., Ray T. K., Savage R. C., Jr Effects of anti-insulin receptor antibodies on in vivo insulin metabolism. Diabetes. 1985 Apr;34(4):342–346. doi: 10.2337/diab.34.4.342. [DOI] [PubMed] [Google Scholar]
  2. Cushman S. W. Structure-function relationships in the adipose cell. I. Ultrastructure of the isolated adipose cell. J Cell Biol. 1970 Aug;46(2):326–341. doi: 10.1083/jcb.46.2.326. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Czech M. P., Lynn W. S. Stimulation of glucose metabolism by lectins in isolated white fat cells. Biochim Biophys Acta. 1973 Feb 28;297(2):368–377. doi: 10.1016/0304-4165(73)90084-6. [DOI] [PubMed] [Google Scholar]
  4. De Pirro R., Rossetti L., Montemurro A., Lauro R., Gammeltoft S., Maddux B. A., Goldfine I. D. Human autoantibodies directed against the human, but not the rat, insulin receptor. J Clin Endocrinol Metab. 1985 Nov;61(5):986–989. doi: 10.1210/jcem-61-5-986. [DOI] [PubMed] [Google Scholar]
  5. De Pirro R., Roth R. A., Rossetti L., Goldfine I. D. Characterization of the serum from a patient with insulin resistance and hypoglycemia. Evidence for multiple populations of insulin receptor antibodies with different receptor binding and insulin-mimicking activities. Diabetes. 1984 Mar;33(3):301–304. doi: 10.2337/diab.33.3.301. [DOI] [PubMed] [Google Scholar]
  6. Drell D. W., Notkins A. L. Multiple immunological abnormalities in patients with type 1 (insulin-dependent) diabetes mellitus. Diabetologia. 1987 Mar;30(3):132–143. doi: 10.1007/BF00274217. [DOI] [PubMed] [Google Scholar]
  7. Flier J. S., Kahn C. R., Roth J., Bar R. S. Antibodies that impair insulin receptor binding in an unusual diabetic syndrome with severe insulin resistance. Science. 1975 Oct 3;190(4209):63–65. doi: 10.1126/science.170678. [DOI] [PubMed] [Google Scholar]
  8. Fujita-Yamaguchi Y., Choi S., Sakamoto Y., Itakura K. Purification of insulin receptor with full binding activity. J Biol Chem. 1983 Apr 25;258(8):5045–5049. [PubMed] [Google Scholar]
  9. Fujita-Yamaguchi Y., LeBon T. R., Tsubokawa M., Henzel W., Kathuria S., Koyal D., Ramachandran J. Comparison of insulin-like growth factor I receptor and insulin receptor purified from human placental membranes. J Biol Chem. 1986 Dec 15;261(35):16727–16731. [PubMed] [Google Scholar]
  10. Gerbitz K. D., Kemmler W. Method for rapid quantitation and characterization of insulin antibodies. Clin Chem. 1978 Jun;24(6):890–894. [PubMed] [Google Scholar]
  11. Harrison L. C., Flier J. S., Roth J., Karlsson F. A., Kahn C. R. Immunoprecipitation of the insulin receptor: a sensitive assay for receptor antibodies and a specific technique for receptor purification. J Clin Endocrinol Metab. 1979 Jan;48(1):59–65. doi: 10.1210/jcem-48-1-59. [DOI] [PubMed] [Google Scholar]
  12. Jacobs S., Hazum E., Shechter Y., Cuatrecasas P. Insulin receptor: covalent labeling and identification of subunits. Proc Natl Acad Sci U S A. 1979 Oct;76(10):4918–4921. doi: 10.1073/pnas.76.10.4918. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Kahn C. R., Baird K., Filier J. S., Jarrett D. B. Effects of autoantibodies to the insulin receptor on isolated adipocytes. Studies of insulin binding and insulin action. J Clin Invest. 1977 Nov;60(5):1094–1106. doi: 10.1172/JCI108861. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Kaldany A. Autoantibodies to islet cells in diabetes mellitus. Diabetes. 1979 Feb;28(2):102–105. doi: 10.2337/diab.28.2.102. [DOI] [PubMed] [Google Scholar]
  15. Kasuga M., Sasaki N., Kahn C. R., Nissley S. P., Rechler M. M. Antireceptor antibodies as probes of insulinlike growth factor receptor structure. J Clin Invest. 1983 Oct;72(4):1459–1469. doi: 10.1172/JCI111102. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Katzen H. M., Vicario P. P., Mumford R. A., Green B. G. Evidence that the insulin-like activities of concanavalin A and insulin are mediated by a common insulin receptor linked effector system. Biochemistry. 1981 Sep 29;20(20):5800–5809. doi: 10.1021/bi00523a024. [DOI] [PubMed] [Google Scholar]
  17. Kull F. C., Jr, Jacobs S., Su Y. F., Cuatrecasas P. A monoclonal antibody to human insulin receptor. Biochem Biophys Res Commun. 1982 Jun 15;106(3):1019–1026. doi: 10.1016/0006-291x(82)91813-7. [DOI] [PubMed] [Google Scholar]
  18. Ludwig S. M., Faiman C., Dean H. J. Insulin and insulin-receptor autoantibodies in children with newly diagnosed IDDM before insulin therapy. Diabetes. 1987 Apr;36(4):420–425. doi: 10.2337/diab.36.4.420. [DOI] [PubMed] [Google Scholar]
  19. Maron R., Elias D., de Jongh B. M., Bruining G. J., van Rood J. J., Shechter Y., Cohen I. R. Autoantibodies to the insulin receptor in juvenile onset insulin-dependent diabetes. Nature. 1983 Jun 30;303(5920):817–818. doi: 10.1038/303817a0. [DOI] [PubMed] [Google Scholar]
  20. Melez K. A., Harrison L. C., Gilliam J. N., Steinberg A. D. Diabetes is associated with autoimmunity in the New Zealand obese (NZO) mouse. Diabetes. 1980 Oct;29(10):835–840. doi: 10.2337/diacare.20.10.835. [DOI] [PubMed] [Google Scholar]
  21. Nakagawa S., Nakayama H., Sasaki T., Yoshino K., Yu Y. Y. A simple method for the determination of serum free insulin levels in insulin-treated patients. Diabetes. 1973 Aug;22(8):590–600. doi: 10.2337/diab.22.8.590. [DOI] [PubMed] [Google Scholar]
  22. RODBELL M. METABOLISM OF ISOLATED FAT CELLS. I. EFFECTS OF HORMONES ON GLUCOSE METABOLISM AND LIPOLYSIS. J Biol Chem. 1964 Feb;239:375–380. [PubMed] [Google Scholar]
  23. Rechler M. M., Nissley S. P. The nature and regulation of the receptors for insulin-like growth factors. Annu Rev Physiol. 1985;47:425–442. doi: 10.1146/annurev.ph.47.030185.002233. [DOI] [PubMed] [Google Scholar]
  24. Roth R. A., Cassell D. J., Wong K. Y., Maddux B. A., Goldfine I. D. Monoclonal antibodies to the human insulin receptor block insulin binding and inhibit insulin action. Proc Natl Acad Sci U S A. 1982 Dec;79(23):7312–7316. doi: 10.1073/pnas.79.23.7312. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Shimoyama R., Ray T. K., Savage C. R., Jr, Owen O. E., Boden G. In vivo and in vitro effects of antiinsulin receptor antibodies. J Clin Endocrinol Metab. 1984 Nov;59(5):916–923. doi: 10.1210/jcem-59-5-916. [DOI] [PubMed] [Google Scholar]
  26. Shimoyama R., Savage C. R., Jr, Boden G. Effects of antiinsulin receptor antibodies on amino acid uptake by cultured rat hepatocytes. J Clin Endocrinol Metab. 1985 May;60(5):928–933. doi: 10.1210/jcem-60-5-928. [DOI] [PubMed] [Google Scholar]
  27. Taylor S. I., Dons R. F., Hernandez E., Roth J., Gorden P. Insulin resistance associated with androgen excess in women with autoantibodies to the insulin receptor. Ann Intern Med. 1982 Dec;97(6):851–855. doi: 10.7326/0003-4819-97-6-851. [DOI] [PubMed] [Google Scholar]
  28. Tsushima T., Ohmori Y., Murakami H., Shizume K., Hirata Y. Immunoprecipitation of 125I-insulin crosslinked receptor. Diabetologia. 1983 May;24(5):387–390. doi: 10.1007/BF00251830. [DOI] [PubMed] [Google Scholar]

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

RESOURCES