Skip to main content
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
. 1974 Jan;71(1):84–88. doi: 10.1073/pnas.71.1.84

Insulin-Dependent Regulation of Insulin Receptor Concentrations: A Direct Demonstration in Cell Culture

James R Gavin III *, Jesse Roth *, David M Neville Jr , Pierre De Meyts *, Donald N Buell
PMCID: PMC387937  PMID: 4359334

Abstract

Chronic (5-16 hr) exposure of cultured human lymphocytes to 10-8 M insulin at 37° in vitro produced a decrease in insulin receptor concentrations unaccounted for by simple occupancy of sites; acute exposure (0-2 hr) was without effect. These results reproduced observations in vivo where chronic hyperinsulinemia (e.g., 10-8 M insulin in the circulation of obese insulinresistant hyperglycemic mice) is associated with a substantial reduction in the concentration of insulin receptors per cell, while acute hyperinsulinemia in vivo has no effect on receptor concentration. These data suggest a reciprocal relationship between insulin in the extracellular fluid and the concentration of insulin receptors per cell, which is mediated at the target cell itself by intracellular insulin-sensitive regulatory processes and directly affects target-cell sensitivity to hormone.

Keywords: lymphocytes, extracellular fluid, hormone

Full text

PDF
84

Selected References

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

  1. Archer J. A., Gorden P., Gavin J. R., 3rd, Lesniak M. A., Roth J. Insulin receptors in human circulating lymphocytes: application to the study of insulin resistance in man. J Clin Endocrinol Metab. 1973 Apr;36(4):627–633. doi: 10.1210/jcem-36-4-627. [DOI] [PubMed] [Google Scholar]
  2. BERSON S. A., YALOW R. S. THE PRESENT STATUS OF INSULIN ANTAGONISTS IN PLASMA: OCTOBER 1963. Diabetes. 1964 May-Jun;13:247–259. [PubMed] [Google Scholar]
  3. Berson S. A., Yalow R. S. Some current controversies in diabetes research. Diabetes. 1965 Sep;14(9):549–572. doi: 10.2337/diab.14.9.549. [DOI] [PubMed] [Google Scholar]
  4. Drenick E. J., Brickman A. S., Gold E. M. Dissociation of the obesity-hyperinsulinism relationship following dietary restriction and hyperalimentation. Am J Clin Nutr. 1972 Aug;25(8):746–755. doi: 10.1093/ajcn/25.8.746. [DOI] [PubMed] [Google Scholar]
  5. Edidin M., Weiss A. Antigen cap formation in cultured fibroblasts: a reflection of membrane fluidity and of cell motility. Proc Natl Acad Sci U S A. 1972 Sep;69(9):2456–2459. doi: 10.1073/pnas.69.9.2456. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Fahey J. L., Buell D. N., Sox H. C. Proliferation and differentiation of lymphoid cells: studies with human lymphoid cell lines and immunoglobulin synthesis. Ann N Y Acad Sci. 1971 Dec 31;190:221–234. doi: 10.1111/j.1749-6632.1971.tb13537.x. [DOI] [PubMed] [Google Scholar]
  7. Finegold I., Fahey J. L., Granger H. Synthesis of immunoglobulins by human cell lines in tissue culture. J Immunol. 1967 Nov;99(5):839–848. [PubMed] [Google Scholar]
  8. Freychet P., Laudat M. H., Laudat P., Rosselin G., Kahn C. R., Gorden P., Roth J. Impairment of insulin binding to the fat cell plasma membrane in the obese hyperglycemic mouse. FEBS Lett. 1972 Sep 15;25(2):339–342. doi: 10.1016/0014-5793(72)80519-2. [DOI] [PubMed] [Google Scholar]
  9. Freychet P., Roth J., Neville D. M., Jr Insulin receptors in the liver: specific binding of ( 125 I)insulin to the plasma membrane and its relation to insulin bioactivity. Proc Natl Acad Sci U S A. 1971 Aug;68(8):1833–1837. doi: 10.1073/pnas.68.8.1833. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Freychet P., Roth J., Neville D. M., Jr Monoiodoinsulin: demonstration of its biological activity and binding to fat cells and liver membranes. Biochem Biophys Res Commun. 1971 Apr 16;43(2):400–408. doi: 10.1016/0006-291x(71)90767-4. [DOI] [PubMed] [Google Scholar]
  11. Gavin J. R., 3rd, Gorden P., Roth J., Archer J. A., Buell D. N. Characteristics of the human lymphocyte insulin receptor. J Biol Chem. 1973 Mar 25;248(6):2202–2207. [PubMed] [Google Scholar]
  12. Gavin J. R., 3rd, Roth J., Jen P., Freychet P. Insulin receptors in human circulating cells and fibroblasts. Proc Natl Acad Sci U S A. 1972 Mar;69(3):747–751. doi: 10.1073/pnas.69.3.747. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Goldfine I. D., Kahn C. R., Neville D. M., Jr, Roth J., Garrison M. M., Bates R. W. Decreased binding of insulin to its receptors in rats with hormone induced insulin resistance. Biochem Biophys Res Commun. 1973 Aug 6;53(3):852–857. doi: 10.1016/0006-291x(73)90171-x. [DOI] [PubMed] [Google Scholar]
  14. Grey N. J., Goldring S., Kipnis D. M. The effect of fasting, diet, and actinomycin D on insulin secretion in the rat. J Clin Invest. 1970 May;49(5):881–889. doi: 10.1172/JCI106307. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Grey N., Kipnis D. M. Effect of diet composition on the hyperinsulinemia of obesity. N Engl J Med. 1971 Oct 7;285(15):827–831. doi: 10.1056/NEJM197110072851504. [DOI] [PubMed] [Google Scholar]
  16. Kahn C. R., Neville D. M., Jr, Gorden P., Freychet P., Roth J. Insulin receptor defect in insulin resistance: studies in the obese-hyperglycimic mouse. Biochem Biophys Res Commun. 1972 Jul 11;48(1):135–142. doi: 10.1016/0006-291x(72)90354-3. [DOI] [PubMed] [Google Scholar]
  17. Kahn C. R., Neville D. M., Jr, Roth J. Insulin-receptor interaction in the obese-hyperglycemic mouse. A model of insulin resistance. J Biol Chem. 1973 Jan 10;248(1):244–250. [PubMed] [Google Scholar]
  18. Karnovsky M. J., Unanue E. R. Mapping and migration of lymphocyte surface macromolecules. Fed Proc. 1973 Jan;32(1):55–59. [PubMed] [Google Scholar]
  19. Kirschner M. A., Wider J. A., Ross G. T. Leydig cell function in men with gonadotrophin-producing testicular tumors. J Clin Endocrinol Metab. 1970 Apr;30(4):504–511. doi: 10.1210/jcem-30-4-504. [DOI] [PubMed] [Google Scholar]
  20. Kono T., Barham F. W. The relationship between the insulin-binding capacity of fat cells and the cellular response to insulin. Studies with intact and trypsin-treated fat cells. J Biol Chem. 1971 Oct 25;246(20):6210–6216. [PubMed] [Google Scholar]
  21. Lefkowitz R. J., Roth J., Pastan I. ACTH-receptor interaction in the adrenal: a model for the initial step in the action of hormones that stimulate adenyl cyclase. Ann N Y Acad Sci. 1971 Dec 30;185:195–209. doi: 10.1111/j.1749-6632.1971.tb45249.x. [DOI] [PubMed] [Google Scholar]
  22. Lefkowitz R. J., Roth J., Pastan I. Radioreceptor assay of adrenocorticotropic hormone: new approach to assay of polypeptide hormones in plasma. Science. 1970 Nov 6;170(3958):633–635. doi: 10.1126/science.170.3958.633. [DOI] [PubMed] [Google Scholar]
  23. Lefkowitz R. J., Roth J., Pricer W., Pastan I. ACTH receptors in the adrenal: specific binding of ACTH-125I and its relation to adenyl cyclase. Proc Natl Acad Sci U S A. 1970 Mar;65(3):745–752. doi: 10.1073/pnas.65.3.745. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Lesniak M. A., Roth J., Gorden P., Gavin J. R., 3rd Human growth hormone radioreceptor assay using cultured human lymphocytes. Nat New Biol. 1973 Jan 3;241(105):20–22. doi: 10.1038/newbio241020a0. [DOI] [PubMed] [Google Scholar]
  25. Lin S. Y., Ellis H., Weisblum B., Goodfriend T. L. Preparation and properties of iodinated angiotensins. Biochem Pharmacol. 1970 Mar;19(3):651–662. doi: 10.1016/0006-2952(70)90227-3. [DOI] [PubMed] [Google Scholar]
  26. Lin S. Y., Goodfriend T. L. Angiotensin receptors. Am J Physiol. 1970 May;218(5):1319–1328. doi: 10.1152/ajplegacy.1970.218.5.1319. [DOI] [PubMed] [Google Scholar]
  27. Moore G. E., Ito E., Ulrich K., Sandberg A. A. Culture of human leukemia cells. Cancer. 1966 May;19(5):713–723. doi: 10.1002/1097-0142(196605)19:5<713::aid-cncr2820190518>3.0.co;2-y. [DOI] [PubMed] [Google Scholar]
  28. Olefsky J., Farquhar J. W., Reaven G. Relationship between fasting plasma insulin level and resistance to insulin-mediated glucose uptake in normal and diabetic subjects. Diabetes. 1973 Jul;22(7):507–513. doi: 10.2337/diab.22.7.507. [DOI] [PubMed] [Google Scholar]
  29. Porte D., Jr, Bagdade J. D. Human insulin secretion: as integrated approach. Annu Rev Med. 1970;21:219–240. doi: 10.1146/annurev.me.21.020170.001251. [DOI] [PubMed] [Google Scholar]
  30. Rabinowitz D. Some endocrine and metabolic aspects of obesity. Annu Rev Med. 1970;21:241–258. doi: 10.1146/annurev.me.21.020170.001325. [DOI] [PubMed] [Google Scholar]
  31. Raff M. C., De Petris S. Movement of lymphocyte surface antigens and receptors: the fluid nature of the lymphocyte plasma membrane and its immunological significance. Fed Proc. 1973 Jan;32(1):48–54. [PubMed] [Google Scholar]
  32. Roth J. Peptide hormone binding to receptors: a review of direct studies in vitro. Metabolism. 1973 Aug;22(8):1059–1073. doi: 10.1016/0026-0495(73)90225-4. [DOI] [PubMed] [Google Scholar]
  33. Tashjian A. H., Jr, Melvin E. W. Medullary carcinoma of the thyroid gland. Studies of thyrocalcitonin in plasma and tumor extracts. N Engl J Med. 1968 Aug 8;279(6):279–283. doi: 10.1056/NEJM196808082790602. [DOI] [PubMed] [Google Scholar]
  34. Unanue E. R., Perkins W. D., Karnovsky M. J. Ligand-induced movement of lymphocyte membrane macromolecules. I. Analysis by immunofluorescence and ultrastructural radioautography. J Exp Med. 1972 Oct 1;136(4):885–906. doi: 10.1084/jem.136.4.885. [DOI] [PMC free article] [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