Skip to main content
NCBI home page
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
. 1984 Apr;81(8):2508–2511. doi: 10.1073/pnas.81.8.2508

Antibody against the insulin receptor causes disappearance of insulin receptors in 3T3-L1 cells: a possible explanation of antibody-induced insulin resistance.

C Grunfeld
PMCID: PMC345091  PMID: 6371815

Abstract

The effect of a rabbit antibody induced against the rat insulin receptor (RAR) was tested using cultured 3T3-L1 fat cells. As previously seen with antibodies against the insulin receptor from patients with the type B syndrome of insulin resistance and acanthosis nigricans, RAR acutely mimicked the action of insulin by stimulating deoxyglucose uptake. After prolonged exposure of 3T3-L1 cells to RAR, insulinomimetic activity was lost and the cells became resistant to the action of insulin. This state of insulin resistance is similar to that seen with the human autoantibodies. However, unlike antibody from the patients, RAR did not acutely inhibit the binding of insulin to its receptor; rather, RAR increased the binding of insulin to its receptor by a mechanism consistent with an increase in the affinity of the receptor for insulin. With prolonged exposure to RAR there was a dramatic decrease in insulin-receptor binding on the treated 3T3-L1 fat cells. These results suggest that antibody against the insulin receptor induces insulin resistance by a mechanism that involves loss of cell-surface insulin receptors.

Full text

PDF
2508

Selected References

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

  1. Caro J. F., Amatruda J. M. Evidence for modulation of insulin action and degradation independently of insulin binding. Am J Physiol. 1981 Mar;240(3):E325–E332. doi: 10.1152/ajpendo.1981.240.3.E325. [DOI] [PubMed] [Google Scholar]
  2. Drachman D. B. Myasthenia gravis (first of two parts). N Engl J Med. 1978 Jan 19;298(3):136–142. doi: 10.1056/NEJM197801192980305. [DOI] [PubMed] [Google Scholar]
  3. 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]
  4. Grunfeld C., Baird K., Van Obberghen E., Kahn C. R. Glucocorticoid-induced insulin resistance in vitro: evidence for both receptor and postreceptor defects. Endocrinology. 1981 Nov;109(5):1723–1730. doi: 10.1210/endo-109-5-1723. [DOI] [PubMed] [Google Scholar]
  5. Grunfeld C., Van Obberghen E., Karlsson F. A., Kahn C. R. Antibody-induced desensitization of the insulin receptor. Studies of the mechanism of desensitization in 3T3-L1 fatty fibroblasts. J Clin Invest. 1980 Nov;66(5):1124–1134. doi: 10.1172/JCI109942. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Harmon J. T., Kahn C. R., Kempner E. S., Schlegel W. Characterization of the insulin receptor in its membrane environment by radiation inactivation. J Biol Chem. 1980 Apr 25;255(8):3412–3419. [PubMed] [Google Scholar]
  7. Jacobs S., Chang K. J., Cuatrecasas P. Antibodies to purified insulin receptor have insulin-like activity. Science. 1978 Jun 16;200(4347):1283–1284. doi: 10.1126/science.663609. [DOI] [PubMed] [Google Scholar]
  8. Jacobs S., Hazum E., Cuatrecasas P. The subunit structure of rat liver insulin receptor. Antibodies directed against the insulin-binding subunit. J Biol Chem. 1980 Jul 25;255(14):6937–6940. [PubMed] [Google Scholar]
  9. Kahn C. R., Baird K. L., Flier J. S., Grunfeld C., Harmon J. T., Harrison L. C., Karlsson F. A., Kasuga M., King G. L., Lang U. C. Insulin receptors, receptor antibodies, and the mechanism of insulin action. Recent Prog Horm Res. 1981;37:477–538. doi: 10.1016/b978-0-12-571137-1.50015-3. [DOI] [PubMed] [Google Scholar]
  10. Kahn C. R., Flier J. S., Bar R. S., Archer J. A., Gorden P., Martin M. M., Roth J. The syndromes of insulin resistance and acanthosis nigricans. Insulin-receptor disorders in man. N Engl J Med. 1976 Apr 1;294(14):739–745. doi: 10.1056/NEJM197604012941401. [DOI] [PubMed] [Google Scholar]
  11. Karlsson F. A., Grunfeld C., Kahn C. R., Roth J. Regulation of insulin receptors and insulin responsiveness in 3T3-L1 fatty fibroblasts. Endocrinology. 1979 May;104(5):1383–1392. doi: 10.1210/endo-104-5-1383. [DOI] [PubMed] [Google Scholar]
  12. Karlsson F. A., Van Obberghen E., Grunfeld C., Kahn C. R. Desensitization of the insulin receptor at an early postreceptor step by prolonged exposure to antireceptor antibody. Proc Natl Acad Sci U S A. 1979 Feb;76(2):809–813. doi: 10.1073/pnas.76.2.809. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Klotz I. M. Numbers of receptor sites from Scatchard graphs: facts and fantasies. Science. 1982 Sep 24;217(4566):1247–1249. doi: 10.1126/science.6287580. [DOI] [PubMed] [Google Scholar]
  14. Muggeo M., Kahn C. R., Bar R. S., Rechler M., Flier J. S., Roth J. The underlying insulin receptor in patients with antireceptor autoantibodies: demonstration of normal binding and immunological properties. J Clin Endocrinol Metab. 1979 Jul;49(1):110–119. doi: 10.1210/jcem-49-1-110. [DOI] [PubMed] [Google Scholar]
  15. Munson P. J., Rodbard D. Number of receptor sites from Scatchard and Klotz graphs: a constructive critique. Science. 1983 May 27;220(4600):979–981. doi: 10.1126/science.6302842. [DOI] [PubMed] [Google Scholar]
  16. Ronnett G. V., Knutson V. P., Lane M. D. Insulin-induced down-regulation of insulin receptors in 3T3-L1 adipocytes. Altered rate of receptor inactivation. J Biol Chem. 1982 Apr 25;257(8):4285–4291. [PubMed] [Google Scholar]
  17. Rosen O. M., Smith C. J., Fung C., Rubin C. S. Development of hormone receptors and hormone responsiveness in vitro. Effect of prolonged insulin treatment on hexose uptake in 3T3-L1 adipocytes. J Biol Chem. 1978 Oct 25;253(20):7579–7583. [PubMed] [Google Scholar]
  18. Roth R. A., Maddux B. A., Cassell D. J., Goldfine I. D. Regulation of the insulin receptor by a monoclonal anti-receptor antibody. Evidence that receptor down regulation can be independent of insulin action. J Biol Chem. 1983 Oct 25;258(20):12094–12097. [PubMed] [Google Scholar]
  19. Taylor S. I., Marcus-Samuels B. Anti-receptor antibodies mimic the effect of insulin to down-regulate insulin receptors in cultured human lymphoblastoid (IM-9) cells. J Clin Endocrinol Metab. 1984 Jan;58(1):182–186. doi: 10.1210/jcem-58-1-182. [DOI] [PubMed] [Google Scholar]

Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences

RESOURCES