Skip to main content
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1976 Dec;58(6):1435–1441. doi: 10.1172/JCI108599

Correlation between insulin receptor binding in isolated fat cells and insulin sensitivity in obese human subjects.

L C Harrison, F I Martin, R A Melick
PMCID: PMC333315  PMID: 993352

Abstract

This study examined the relationship between receptor binding of insulin in a metabolically significant target tissue in vitro and sensitivity to insulin in vivo in obese human subjects. Specific insulin binding was measured at 24 degrees C in isolated enlarged fat cells obtained from 16 patients, by observing the effect of increasing concentrations of unlabeled insulin on the binding of [125I]insulin. Scratchard plots of the binding data were curvilinear with an upward concavity, similarity shaped, and essentially parallel. Kinetic studies on the dissociation of [125I]insulin from fat cells indicated that these curvilinear Scratchard plots could be explained by the presence of site:site interactions of the negative cooperative type. Differences in binding between individual patients were predominantly due to differences in the numbers of receptor sites whether expressed in relation to cell number, cell volume, or cell surface area. These findings were not accounted for by differences in [125I]insulin degradation. Acute exposure of adipose tissue to insulin in vitro had no significant effect on [125I]insulin binding to isolated cells. The number of receptor sites was directly correlated with insulin sensitivity in vivo, measured as the rate constant (Kitt) for the fall in blood glucose after intravenous insulin, and was inversely correlated with the level of fasting plasma insulin. These findings corroborate those from other studies using human mononuclear leukocytes and various tissues from the obese mouse, which indicate that decreased insulin binding is a characteristic feature of insulin resistance in obesity.

Full text

PDF
1435

Selected References

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

  1. Amatruda J. M., Livingston J. N., Lockwood D. H. Insulin receptor: role in the resistance of human obesity to insulin. Science. 1975 Apr 18;188(4185):264–266. doi: 10.1126/science.164059. [DOI] [PubMed] [Google Scholar]
  2. Archer J. A., Gorden P., Roth J. Defect in insulin binding to receptors in obese man. Amelioration with calorie restriction. J Clin Invest. 1975 Jan;55(1):166–174. doi: 10.1172/JCI107907. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Björntorp P., Berchtold P., Holm J., Larsson B. The glucose uptake of human adipose tissue in obesity. Eur J Clin Invest. 1971 Sep;1(6):480–485. doi: 10.1111/j.1365-2362.1971.tb00559.x. [DOI] [PubMed] [Google Scholar]
  4. De Meyts P., Roth J. Cooperativity in ligand binding: a new graphic analysis. Biochem Biophys Res Commun. 1975 Oct 27;66(4):1118–1126. doi: 10.1016/0006-291x(75)90473-8. [DOI] [PubMed] [Google Scholar]
  5. Forgue M. E., Freychet P. Insulin receptors in the heart muscle. Demonstration of specific binding sites and impairment of insulin binding in the plasma membrane of the obese hyperglycemic mouse. Diabetes. 1975 Aug;24(8):715–723. doi: 10.2337/diab.24.8.715. [DOI] [PubMed] [Google Scholar]
  6. Freychet P., Kahn R., Roth J., Neville D. M., Jr Insulin interactions with liver plasma membranes. Independence of binding of the hormone and its degradation. J Biol Chem. 1972 Jun 25;247(12):3953–3961. [PubMed] [Google Scholar]
  7. 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]
  8. Gliemann J., Osterlind K., Vinten J., Gammeltoft S. A procedure for measurement of distribution spaces in isolated fat cells. Biochim Biophys Acta. 1972 Nov 24;286(1):1–9. doi: 10.1016/0304-4165(72)90082-7. [DOI] [PubMed] [Google Scholar]
  9. Harrison L. C., King-Roach A. P. Cell size and glucose oxidation rate in adipose tissue from non-diabetic and diabetic obese human subjects. Clin Sci Mol Med. 1976 Mar;50(3):171–175. doi: 10.1042/cs0500171. [DOI] [PubMed] [Google Scholar]
  10. Hill A. V. The Combinations of Haemoglobin with Oxygen and with Carbon Monoxide. I. Biochem J. 1913 Oct;7(5):471–480. doi: 10.1042/bj0070471. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Kahn C. R., Freychet P., Roth J., Neville D. M., Jr Quantitative aspects of the insulin-receptor interaction in liver plasma membranes. J Biol Chem. 1974 Apr 10;249(7):2249–2257. [PubMed] [Google Scholar]
  12. 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]
  13. Olefsky J. M. Decreased insulin binding to adipocytes and circulating monocytes from obese subjects. J Clin Invest. 1976 May;57(5):1165–1172. doi: 10.1172/JCI108384. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Olefsky J. M., Jen P., Reaven G. M., Alto P. Insulin binding to isolated human adipocytes. Diabetes. 1974 Jul;23(7):565–571. doi: 10.2337/diab.23.7.565. [DOI] [PubMed] [Google Scholar]
  15. Olefsky J. M., Reaven G. M. Effects of age and obesity on insulin binding to isolated adipocytes. Endocrinology. 1975 Jun;96(6):1486–1498. doi: 10.1210/endo-96-6-1486. [DOI] [PubMed] [Google Scholar]
  16. PEARSON R. S., BAYLIS J. H., SMELLIE H. C. Treatment of chronic asthma with prednisolone and the newer steroids. Br Med J. 1961 Feb 4;1(5222):315–319. doi: 10.1136/bmj.1.5222.315. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Pearson M. J., Martin F. I. The separation of total plasma insulin from binding proteins using gel filtration: its application to the measurement of rate of insulin disappearance. Diabetologia. 1970 Dec;6(6):581–585. doi: 10.1007/BF00418225. [DOI] [PubMed] [Google Scholar]
  18. 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]
  19. 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]
  20. Roth J., Kahn C. R., Lesniak M. A., Gorden P., De Meyts P., Megyesi K., Neville D. M., Jr, Gavin J. R., 3rd, Soll A. H., Freychet P. Receptors for insulin, NSILA-s, and growth hormone: applications to disease states in man. Recent Prog Horm Res. 1975;31:95–139. doi: 10.1016/b978-0-12-571131-9.50007-4. [DOI] [PubMed] [Google Scholar]
  21. 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]
  22. Salans L. B., Bray G. A., Cushman S. W., Danforth E., Jr, Glennon J. A., Horton E. S., Sims E. A. Glucose metabolism and the response to insulin by human adipose tissue in spontaneous and experimental obesity. Effects of dietary composition and adipose cell size. J Clin Invest. 1974 Mar;53(3):848–856. doi: 10.1172/JCI107625. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Soli A. H., Kahn C. R., Neville D. M., Jr, Roth J. Insulin receptor deficiency in genetic and acquired obesity. J Clin Invest. 1975 Oct;56(4):769–780. doi: 10.1172/JCI108155. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Soll A. H., Goldfine I. D., Roth J., Kahn C. R. Thymic lymphocytes in obese (ob-ob) mice. A mirror of the insulin receptor defect in liver and fat. J Biol Chem. 1974 Jul 10;249(13):4127–4131. [PubMed] [Google Scholar]
  25. YALOW R. S., BERSON S. A. Immunoassay of endogenous plasma insulin in man. J Clin Invest. 1960 Jul;39:1157–1175. doi: 10.1172/JCI104130. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. de Meyts P., Roth J., Neville D. M., Jr, Gavin J. R., 3rd, Lesniak M. A. Insulin interactions with its receptors: experimental evidence for negative cooperativity. Biochem Biophys Res Commun. 1973 Nov 1;55(1):154–161. doi: 10.1016/s0006-291x(73)80072-5. [DOI] [PubMed] [Google Scholar]

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

RESOURCES