Receptor Defects in Genetic Forms of Extreme Insulin Resistance

  • Simeon I. Taylor
Part of the Biochemical Endocrinology book series (BIOEND, volume 1)


The responsiveness of target cells to insulin is carefully regulated under many physiological conditions (Grunberger et al., 1983; Olefsky, 1981). Thus, two mechanisms work in concert to regulate the biological effect of insulin upon target cells: (1) changes in circulating levels of insulin in plasma; and (2) alterations in the sensitivity of the target cell to insulin. Abnormalities in the regulation of insulin sensitivity contribute importantly to the pathophysiology of many disease states: e.g., obesity, type II diabetes (non-insulin-dependent diabetes mellitus), acromegaly, and Cushing’s syndrome.


Insulin Resistance Insulin Receptor Apparent Molecular Weight Insulin Binding Subunit Structure 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Bar, R. S., Muggeo, M., Kahn, C. R., Gorden, P., and Roth, J., 1980, Characterization of insulin receptors in patients with the syndrome of insulin resistance and acanthosis nigricans, Diabetologia 18:209.PubMedCrossRefGoogle Scholar
  2. Bar, R. S., Muggeo, M., Roth, J., Kahn, C. R., Havrankova, J., and Imperato-McGinley, J., 1978, Insulin resistance, acanthosis nigricans, and normal insulin receptors in a young woman: Evidence for a post-receptor defect, J. Clin. Endocrinol. Metab. 47:620.PubMedCrossRefGoogle Scholar
  3. Barnes, N. D., Polumbo, P. J., Hayles, A. B., and Folgar, H., 1974, Insulin resistance, skin changes, and virilization: A recessively inherited syndrome possibly due to pineal gland dysfunction, Diabetologia 10:285.PubMedGoogle Scholar
  4. D’Ercole, A. J., Underwood, L. E., Groelke, J., and Plet, A., 1979, Leprechaunism: Studies of the relationship among hyperinsulinism, insulin resistance, and growth retarda-tion, J. Clin. Endocrinol. Metab. 48:495.PubMedCrossRefGoogle Scholar
  5. Donohue, W. L., and Uchida, I., 1954, Leprechaunism. A euphuism for a rare familial disorder, J. Pediatrics 45:505.CrossRefGoogle Scholar
  6. Flier, J. S., Kahn, C. R., Jarrett, D. B., and Roth, J., 1976, Characterization of antibodies to the insulin receptor: A cause of insulin-resistant diabetes in man, J. Clin. Invest. 58:1442.PubMedCrossRefGoogle Scholar
  7. Flier, J. S., Young, J. B., and Landsberg, L., 1980, Familial insulin resistance with acanthosis nigricans, acral hyper-trophy, and muscle cramps, N. Eng. J. Med. 303:970.CrossRefGoogle Scholar
  8. Friedenberg, G. R., White, N., Cataland, S., O’Dorisio, T. M., Sotos, J. F., and Santiago, J. V., 1981, Diabetes respon-sive to intravenous but not subcutaneous insulin: Effect-iveness of aprotinin, N. Eng. J. Med. 305:363.CrossRefGoogle Scholar
  9. Gabbay, K. H., Bergenstal, R. M., Wolff, J., Mako, M. E., and Rubenstein, A. H., 1979, Familial hyperproinsulinemia: Partial characterization of circulating proinsulin-like material, Proc. Natl. Acad. Sci. USA 76:2881PubMedCrossRefGoogle Scholar
  10. Gavin, J. R., III, Roth, J., Neville, D. M. Jr., De Meyts, P., and Buell, D. N., 1974, Insulin-dependent regulation of insulin receptor concentrations: A direct demonstration in cell culture, Proc. Natl. Acad. Sci. USA 71:84.PubMedCrossRefGoogle Scholar
  11. Given, B. D., Mako, M. E., Tager, H., Baldwin, D., Markese, J., Rubenstein, A. H., Olefsky, J., Kobayashi, M., Kolterman, O., and Poucher, R., 1980, Diabetes due to secretion of an abnormal insulin, N. Eng. J. Med. 302:129.CrossRefGoogle Scholar
  12. Grunberger, G., Taylor, S. I., Dons, R. F., and Gorden, P., 1983, Insulin receptor in normal and disease states, Clin. Endocrinol. Metab. (in press).Google Scholar
  13. Haneda, M., Bergenstal, R., Freidenberg, G., Wishner, W., Blix, P., Provow, S., Polonsky, K., and Rubenstein, A., 1982, Familial diabetes associated with a possible structural defect in circulating insulin, Diabetes 31 (suppl. 2):4A (abstract #13).Google Scholar
  14. Hedo, J. A., Harrison, L. C., and Roth, J., 1981, Binding of insulin receptors to lectins: Evidence for common carbo-hydrate determinants on several membrane receptors, Biochemistry 20:3385. and II and their relationship to the insulin receptor, J. Biol. Chem. 257:5038.PubMedCrossRefGoogle Scholar
  15. Olefsky, J. M., 1981, Insulin resistance and insulin action: An in vitro and in vivo perspective, Diabetes 30:148.PubMedGoogle Scholar
  16. Perez-Corral, F., de la Vina, S., Carbo, M., Barrio, R., Yturriaga, R., Perez-Meceda, B., Alonso, M., and SerranoRios, M., 1980, Rabson syndrome: Model of insulin resist-ance due to decreased number and affinity of insulin receptors in erythrocytes, Diabetologia 19:306 (abstract).Google Scholar
  17. Pilch, P. F., and Czech, M., 1979, Interaction of cross-linking agents with the insulin effector system of isolated fat cells, J. Biol. Chem. 254:3375.PubMedGoogle Scholar
  18. Podskalny, J. M., and Kahn, C. R., 1982a, Cell culture studies on patients with extreme insulin resistance. I. Receptor defects on cultured fibroblasts, J. Clin. Endo. Metab. 54:261.CrossRefGoogle Scholar
  19. Podskalny, J. M., and Kahn, C. R., 1982b, Cell culture studies on patients with extreme insulin resistance. II. Abnormal biological responses in cultured fibroblasts, J. Clin. Endocrinol. Metab. 54:269.PubMedCrossRefGoogle Scholar
  20. Rabson, S. M., and Mendenhall, E. N., 1956, Familial hypertrophy of pineal body, hyperplasia of adrenal cortex and diabetes mellitus, Amer. J. Clin. Path. 26:283.Google Scholar
  21. Rechler, M. M., Nissley, S. P., Podskalny, J. M., Moses, A. C., and Fryklund, L., 1977, Identification of a receptor for somatomedin-like polypeptides in human fibroblasts, J. Clin. Endocrinol. Metab. 44:820.PubMedCrossRefGoogle Scholar
  22. Robbins, D. C., Blix, P. M., Rubenstein, A. H., Kanazawa, Y., Kosaka, K., and Tager, H. S., 1981, A human proinsulin variant at arginine 65, Nature 291:679.PubMedCrossRefGoogle Scholar
  23. Rosenberg, A. M., Haworth, J. C., Degroot, G. W., Trevenen, C. L., and Rechler, M. M., 1980, A case of leprechaunism with severe hyperinsulinemia, Am. J. Pis. Child 134:170.Google Scholar
  24. Roth, J., and Grunfeld, C., 1981, Endocrine systems: Mechanisms of disease, target cells, and receptors, in: “Textbook of Endocrinology”, R. H. Williams, ed., p. 15, Philadelphia: W. B. Saunders, p. 1270.Google Scholar
  25. Scarlett, J. A., Kolterman, O. G., Moore, P., Saekow, M., Insel, J., Griffin, J., Mako, M., Rubenstein, A. H., Olefsky, J. M., 1982, Insulin resistance and diabetes due to a genetic defect in insulin receptors, J. Clin. Endocrinol. Metab. 55:123.PubMedCrossRefGoogle Scholar
  26. Schilling, E. E., Rechler, M. M., Grunfeld, C., and Rosenberg, A. M., 1979, Primary defect of insulin receptors in skin fibroblasts cultured from an infant with leprechaunism and insulin resistance, Proc. Natl. Acad. Sci. USA 76:5877.PubMedCrossRefGoogle Scholar
  27. Huseman, C., Johanson, A., Varma, M., and Blizzard, R. M., 1978, Congenital lipodystrophy: An endocrine study in three siblings. I. Disorders of carbohydrate metabolism, J. Pediatr. 93:221.PubMedCrossRefGoogle Scholar
  28. Jacobs, S., Hazum, E., Shechter, Y., and Cuatrecasas, P., 1979, Insulin receptor: Covalent labeling and identification of subunits, Proc. Natl. Acad. Sci. USA 76:4918.PubMedCrossRefGoogle Scholar
  29. Kahn, C. R., Flier, J. S., Bar, R. S., Archer, J. A., Gorden, P., Martin, M. M., and Roth, J., 1976, The syndromes of insulin resistance and acanthosis nigricans. Insulin-receptor disorders in man, N. Eng. J. Med. 294:739.CrossRefGoogle Scholar
  30. Kahn, C. R., and Podskalny, J. R., 1980, Demonstration of a primary (? genetic) defect in insulin receptors in fibroblasts from a patient with the syndrome of insulin resist-ance and acanthosis nigricans type A, J. Clin. Endocrinol. Metab. 50:1139.PubMedCrossRefGoogle Scholar
  31. Kahn, C. R., and Rosenthal, A. S., 1979, Immunologic reactions to insulin: Insulin allergy, insulin resistance, and the autoimmune insulin syndrome, Diabetes Care 2:283.PubMedGoogle Scholar
  32. Kasuga, M., Kahn, C. R., Hedo, J. A., Van Obberghen, E., Yamada, K. M., 1981a, Insulin-induced receptor loss in cultured human lymphocytes is due to accelerated receptor degrada-tion, Proc. Natl. Acad. Sci. USA 78:6917.PubMedCrossRefGoogle Scholar
  33. Kasuga, M., Van Obberghen, E., Nissley, S. P., and Rechler, M. M., 1981b, Demonstration of two subtypes of insulin-like growth factor receptors by affinity cross-linking, J. Biol. Chem. 256:5308.Google Scholar
  34. Knight, A. B., Rechler, M. M., Romanus, J. A., Van ObberghenSchilling, E. E., and Nissley, S. P., 1981, Stimulation of glucose incorporation and amino acid transport by insulin and an insulin-like growth factor in fibroblasts with defective insulin receptors cultured from a patient with leprechaunism, Proc. Natl. Acad. Sci. USA 78:2554.PubMedCrossRefGoogle Scholar
  35. Kobayashi, M., Olefsky, J. M., Elders, J., Mako, M. E., Given, B. D., Schedewie, H. K., Fiser, R. H., Hintz, R. L., Horner, J. A., Rubenstein, A. H., 1978, Insulin resistance due to a defect distal to the insulin receptor: Demon-stration in a patient with leprechaunism, Proc. Natl. Acad. Sci. USA 75:3469.PubMedCrossRefGoogle Scholar
  36. Kono, T., and Barham, F. W., 1971, The relationship between the insulin-binding capacity of fat cells and the cellular respone to insulin, J. Biol. Chem. 246:6210.PubMedGoogle Scholar
  37. Massague, J., and Czech, M., 1982, The subunit structures of two distinct receptors for insulin-like growth factors IGoogle Scholar
  38. Taylor, S. I., and Leventhal, S., 1982, Absence of positive cooperativity in insulin receptors from a patient with congenital extreme insulin resistance (leprechaunism), Diabetes 3l:l3lA (abstract #501).Google Scholar
  39. Taylor, S. I., Roth, J., Blizzard, R. M., and Elders, M. J., 1981, Qualitative abnormalities in insulin binding in a patient with extreme insulin resistance: Decreased sensi-tivity to alterations in temperature and pH, Proc. Natl. Acad. Sci. USA 78:7157.PubMedCrossRefGoogle Scholar
  40. Taylor, S. I., Samuels, B., Roth, J., Kasuga, M., Hedo, J. A., Gorden, P., Brasel, D. E., Pokora, T., and Engel, R. R., 1982a, Decreased insulin binding in cultured lymphocytes from patients with extreme insulin resistance, J. Clin. Endocrinol. Metab. 54:919.PubMedCrossRefGoogle Scholar
  41. Taylor, S. I., Hedo, J. A., Underhill, L. H., Kasuga, M., Elders, M. J., and Roth, J., 1982b, Extreme insulin resist-ance 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. 55:1108.PubMedCrossRefGoogle Scholar
  42. Taylor, S. I., Underhill, L. H., Roth, J., Serrano,Rios, M., and Blizzard, R. M., 1983, Decreased insulin binding to cultured cells from a patient with the Rabson-Mendenhall syndrome: Dichotomy between studies with cultured lympho-cytes and cultured fibroblasts, J. Clin. Endocrinol. Metab. (in press)Google Scholar
  43. Van Obberghen, E., Kasuga, M., Le Cam, A., Hedo, J. A., Itin, A., and Harrison, L. C., 1981, Biosynthetic labeling of insulin receptors: Studies of subunits in cultured human IM-9 lymphocytes, Proc. Natl. Acad. Sci. USA 78:1052.PubMedCrossRefGoogle Scholar
  44. Wachslicht-Rodbard, H., Muggeo, M., Kahn, C. R., Saviolakis, G. A., Harrison, L. C., and Flier, J. A., 1981, Hetero-geneity of the insulin-receptor interaction in lipostrophic diabetes, J. Clin. Endocrinol. Metab. 52:416.PubMedCrossRefGoogle Scholar
  45. Waelbroeck, M., 1982, The pH dependence of insulin binding, J. Biol. Chem. 257:8284.PubMedGoogle Scholar
  46. Waelbroeck, M., Van Obberghen, E., and De Meyts, P., 1979, Thermodynamics of the interaction of insulin with its receptor, J. Biol. Chem. 254:7736.PubMedGoogle Scholar
  47. West, R. J., and Leonard, J. V., 1980, Familial insulin resist-ance with pineal hyperplasia: Metabolic studies and effect of hypophysectomy, Arch. Pis. Child 55:619.CrossRefGoogle Scholar
  48. West, R. J., Lloyd, J. K., and Turner, W. M. L., 1975, Familial insulin-resistant diabetes, multiple somatic anomalies, and pineal hyperplasia, Archs. Dis. Child 50:703.CrossRefGoogle Scholar

Copyright information

© Plenum Press, New York 1984

Authors and Affiliations

  • Simeon I. Taylor
    • 1
    • 2
  1. 1.Diabetes BranchNational Institute of Arthritis, Diabetes, Digestive and Kidney DiseasesUSA
  2. 2.National Institutes of HealthBethesdaUSA

Personalised recommendations