Skip to main content
NCBI home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1985 Dec;76(6):2355–2361. doi: 10.1172/JCI112247

Insulin receptor biosynthesis in cultured lymphocytes from insulin-resistant patients.

J A Hedo, V Y Moncada, S I Taylor
PMCID: PMC424373  PMID: 4077982

Abstract

In some patients with genetic forms of extreme insulin resistance, the cause of insulin resistance is a marked (greater than or equal to 90%) reduction in the number of insulin receptors on the cell surface. In the present work, we describe studies of insulin receptor biosynthesis in Epstein-Barr virus (EBV)-transformed lymphocytes from three patients (A-1, A-5, and A-8) with type A extreme insulin resistance. Insulin receptors are composed of two major glycoprotein subunits (apparent molecular weight [Mr] of 135 and 95 kD), which are both derived from a common precursor molecule with Mr of 190 kD. In one patient (A-1), there was a marked reduction in the biosynthesis of both the 190-kD precursor and the mature receptor. Thus, in this patient, the defect appears to occur early in the biosynthetic pathway (i.e., before the synthesis of the 190-kD precursor). In contrast, in two sisters (A-5 and A-8) with type A extreme insulin resistance, biosynthesis of the 190-kD precursor proceeds at a normal rate. However, there appears to be a defect subsequent to the biosynthesis of the 190-kD precursor, but before the insertion of the mature receptor in the plasma membrane. Our observations suggest the existence of at least two distinct types of biosynthetic defects which may give rise to a marked reduction in the number of insulin receptors on the cell surface. In addition, for comparison, we have studied receptor biosynthesis in cultured EBV lymphocytes from a fourth patient (A-7) with type A extreme insulin resistance. Although the cells of patient A-7 have a normal number of insulin receptors, we have detected subtle abnormalities in the posttranslational processing of the insulin receptor precursor, which may be a biochemical marker for a postbinding defect that causes insulin resistance in this patient.

Full text

PDF
2355

Images in this article

2356Image
on p.2356
2356Image
on p.2356
2358Image
on p.2358
2358Image
on p.2358
2358Image
on p.2358
2358Image
on p.2358
2358Image
on p.2358
2358Image
on p.2358
2358Image
on p.2358
2358Image
on p.2358
2359Image
on p.2359
2359Image
on p.2359
2359Image
on p.2359
2359Image
on p.2359

Selected References

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

  1. Bar R. S., Muggeo M., Kahn C. R., Gorden P., Roth J. Characterization of insulin receptors in patients with the syndromes of insulin resistance and acanthosis nigricans. Diabetologia. 1980 Mar;18(3):209–216. doi: 10.1007/BF00251918. [DOI] [PubMed] [Google Scholar]
  2. Bar R. S., Muggeo M., Roth J., Kahn C. R., Havrankova J., Imperato-McGinley J. Insulin resistance, acanthosis nigricans, and normal insulin receptors in a young woman: evidence for a postreceptor defect. J Clin Endocrinol Metab. 1978 Sep;47(3):620–625. doi: 10.1210/jcem-47-3-620. [DOI] [PubMed] [Google Scholar]
  3. Barnes N. D., Palumbo P. J., Hayles A. B., Folgar H. Insulin resistance, skin changes, and virilization: a recessively inherited syndrome possibly due to pineal gland dysfunction. Diabetologia. 1974 Aug;10(4):285–289. doi: 10.1007/BF02627729. [DOI] [PubMed] [Google Scholar]
  4. Blackshear P. J., Nemenoff R. A., Avruch J. Insulin binds to and promotes the phosphorylation of a Mr 210 000 component of its receptor in detergent extracts of rat liver microsomes. FEBS Lett. 1983 Jul 25;158(2):243–246. doi: 10.1016/0014-5793(83)80587-0. [DOI] [PubMed] [Google Scholar]
  5. Brown M. S., Kovanen P. T., Goldstein J. L. Regulation of plasma cholesterol by lipoprotein receptors. Science. 1981 May 8;212(4495):628–635. doi: 10.1126/science.6261329. [DOI] [PubMed] [Google Scholar]
  6. D'Ercole A. J., Underwood L. E., Groelke J., Plet A. Leprechaunism: studies of the relationship among hyperinsulinism, insulin resistance, and growth retardation. J Clin Endocrinol Metab. 1979 Mar;48(3):495–502. doi: 10.1210/jcem-48-3-495. [DOI] [PubMed] [Google Scholar]
  7. Deutsch P. J., Wan C. F., Rosen O. M., Rubin C. S. Latent insulin receptors and possible receptor precursors in 3T3-L1 adipocytes. Proc Natl Acad Sci U S A. 1983 Jan;80(1):133–136. doi: 10.1073/pnas.80.1.133. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Grunberger G., Comi R. J., Taylor S. I., Gorden P. Tyrosine kinase activity of the insulin receptor of patients with type A extreme insulin resistance: studies with circulating mononuclear cells and cultured lymphocytes. J Clin Endocrinol Metab. 1984 Dec;59(6):1152–1158. doi: 10.1210/jcem-59-6-1152. [DOI] [PubMed] [Google Scholar]
  9. Grunberger G., Taylor S. I., Dons R. F., Gorden P. Insulin receptors in normal and disease states. Clin Endocrinol Metab. 1983 Mar;12(1):191–219. doi: 10.1016/s0300-595x(83)80036-x. [DOI] [PubMed] [Google Scholar]
  10. Grunberger G., Zick Y., Gorden P. Defect in phosphorylation of insulin receptors in cells from an insulin-resistant patient with normal insulin binding. Science. 1984 Mar 2;223(4639):932–934. doi: 10.1126/science.6141638. [DOI] [PubMed] [Google Scholar]
  11. Hedo J. A., Kahn C. R., Hayashi M., Yamada K. M., Kasuga M. Biosynthesis and glycosylation of the insulin receptor. Evidence for a single polypeptide precursor of the two major subunits. J Biol Chem. 1983 Aug 25;258(16):10020–10026. [PubMed] [Google Scholar]
  12. Hedo J. A., Kasuga M., Van Obberghen E., Roth J., Kahn C. R. Direct demonstration of glycosylation of insulin receptor subunits by biosynthetic and external labeling: evidence for heterogeneity. Proc Natl Acad Sci U S A. 1981 Aug;78(8):4791–4795. doi: 10.1073/pnas.78.8.4791. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Jacobs S., Kull F. C., Jr, Cuatrecasas P. Monensin blocks the maturation of receptors for insulin and somatomedin C: identification of receptor precursors. Proc Natl Acad Sci U S A. 1983 Mar;80(5):1228–1231. doi: 10.1073/pnas.80.5.1228. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. 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]
  15. Kasuga M., Kahn C. R., Hedo J. A., Van Obberghen E., Yamada K. M. Insulin-induced receptor loss in cultured human lymphocytes is due to accelerated receptor degradation. Proc Natl Acad Sci U S A. 1981 Nov;78(11):6917–6921. doi: 10.1073/pnas.78.11.6917. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Lehrman M. A., Schneider W. J., Südhof T. C., Brown M. S., Goldstein J. L., Russell D. W. Mutation in LDL receptor: Alu-Alu recombination deletes exons encoding transmembrane and cytoplasmic domains. Science. 1985 Jan 11;227(4683):140–146. doi: 10.1126/science.3155573. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. McElduff A., Hedo J. A., Taylor S. I., Roth J., Gorden P. Insulin receptor degradation is accelerated in cultured lymphocytes from patients with genetic syndromes of extreme insulin resistance. J Clin Invest. 1984 Oct;74(4):1366–1374. doi: 10.1172/JCI111547. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. McNatty K. P., Smith D. M., Makris A., DeGrazia C., Tulchinsky D., Osathanondh R., Schiff I., Ryan K. J. The intraovarian sites of androgen and estrogen formation in women with normal and hyperandrogenic ovaries as judged by in vitro experiments. J Clin Endocrinol Metab. 1980 Apr;50(4):755–763. doi: 10.1210/jcem-50-4-755. [DOI] [PubMed] [Google Scholar]
  19. Olefsky J. M. LIlly lecture 1980. Insulin resistance and insulin action. An in vitro and in vivo perspective. Diabetes. 1981 Feb;30(2):148–162. doi: 10.2337/diab.30.2.148. [DOI] [PubMed] [Google Scholar]
  20. Schilling E. E., Rechler M. M., Grunfeld C., Rosenberg A. M. Primary defect of insulin receptors in skin fibroblasts cultured from an infant with leprechaunism and insulin resistance. Proc Natl Acad Sci U S A. 1979 Nov;76(11):5877–5881. doi: 10.1073/pnas.76.11.5877. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Taylor S. I., Hedo J. A., Underhill L. H., Kasuga M., Elders M. J., Roth J. Extreme insulin resistance in association with abnormally high binding affinity of insulin receptors from a patient with leprechaunism: evidence for a defect intrinsic to the receptor. J Clin Endocrinol Metab. 1982 Dec;55(6):1108–1113. doi: 10.1210/jcem-55-6-1108. [DOI] [PubMed] [Google Scholar]
  22. Taylor S. I., Leventhal S. Defect in cooperativity in insulin receptors from a patient with a congenital form of extreme insulin resistance. J Clin Invest. 1983 Jun;71(6):1676–1685. doi: 10.1172/JCI110922. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Taylor S. I. Receptor defects in patients with extreme insulin resistance. Diabetes Metab Rev. 1985;1(1-2):171–202. doi: 10.1002/dmr.5610010109. [DOI] [PubMed] [Google Scholar]
  24. Taylor S. I., Roth J., Blizzard R. M., Elders M. J. Qualitative abnormalities in insulin binding in a patient with extreme insulin resistance: decreased sensitivity to alterations in temperature and pH. Proc Natl Acad Sci U S A. 1981 Nov;78(11):7157–7161. doi: 10.1073/pnas.78.11.7157. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Taylor S. I., Samuels B., Roth J., Kasuga M., Hedo J. A., Gorden P., Brasel D. E., Pokora T., Engel R. R. Decreased insulin binding in cultured lymphocytes from two patients with extreme insulin resistance. J Clin Endocrinol Metab. 1982 May;54(5):919–930. doi: 10.1210/jcem-54-5-919. [DOI] [PubMed] [Google Scholar]
  26. Taylor S. I., Underhill L. H., Hedo J. A., Roth J., Rios M. S., Blizzard R. M. Decreased insulin binding to cultured cells from a patient with the Rabson-Mendenhall syndrome: dichotomy between studies with cultured lymphocytes and cultured fibroblasts. J Clin Endocrinol Metab. 1983 Apr;56(4):856–861. doi: 10.1210/jcem-56-4-856. [DOI] [PubMed] [Google Scholar]
  27. Tolleshaug H., Hobgood K. K., Brown M. S., Goldstein J. L. The LDL receptor locus in familial hypercholesterolemia: multiple mutations disrupt transport and processing of a membrane receptor. Cell. 1983 Mar;32(3):941–951. doi: 10.1016/0092-8674(83)90079-x. [DOI] [PubMed] [Google Scholar]
  28. Ullrich A., Bell J. R., Chen E. Y., Herrera R., Petruzzelli L. M., Dull T. J., Gray A., Coussens L., Liao Y. C., Tsubokawa M. Human insulin receptor and its relationship to the tyrosine kinase family of oncogenes. 1985 Feb 28-Mar 6Nature. 313(6005):756–761. doi: 10.1038/313756a0. [DOI] [PubMed] [Google Scholar]
  29. Wagman L. D., Lambert S. R., McElduff A., Roth J., Gorden P., Taylor S. I. Downregulation occurs normally in cultured Epstein-Barr virus-transformed lymphocytes from patients with extreme insulin resistance. Discrepancy between downregulation in vivo and in vitro. Diabetes. 1984 May;33(5):421–427. doi: 10.2337/diab.33.5.421. [DOI] [PubMed] [Google Scholar]
  30. Whittaker J., Zick Y., Roth J., Taylor S. I. Insulin-stimulated receptor phosphorylation appears normal in cultured Epstein-Barr virus-transformed lymphocyte cell lines derived from patients with extreme insulin resistance. J Clin Endocrinol Metab. 1985 Feb;60(2):381–386. doi: 10.1210/jcem-60-2-381. [DOI] [PubMed] [Google Scholar]

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

RESOURCES