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Immunoendocrinology: Scientific and Clinical Aspects pp 369–383Cite as

Lessons from Patients with Anti-Insulin Receptor Autoantibodies

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Part of the book series: Contemporary Endocrinology ((COE))

Summary

Type B insulin resistance is a rare syndrome caused by autoantibodies to the insulin receptor. Patients typically present with severe insulin resistance and hyperglycemia, but some manifest hypoglycemia ­following a period of hyperglycemia or hypoglycemia alone. The syndrome is predominantly seen in middle-aged black women. Other clinical features of type B insulin resistance are acanthosis nigricans, hyperandrogenism in premenopausal women, autoimmune disorders, proteinuric renal disease, and hematologic abnormalities. In addition to dysglycemia, the metabolic characteristics of the syndrome include low serum triglyceride levels and high adiponectin levels. The autoantibody acts as an agonist at the insulin receptor at low titers, but functions as an antagonist at high titers. The partial agonist properties of the autoantibody are responsible for the spectrum of glycemic states observed in type B insulin resistance. The treatment of type B insulin resistance has been of limited success to date and protocols addressing multiple components of the underlying autoimmune process are being developed.

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References

  1. Lindstrom JM. Acetylcholine receptors and myasthenia. Muscle Nerve 2000;23(4):453–477.

    Article  PubMed  CAS  Google Scholar 

  2. Toyka KV, Drachman DB, Griffin DE, et al. Myasthenia gravis. Study of humoral immune mechanisms by passive transfer to mice. N Engl J Med 1977;296(3):125–131.

    Article  PubMed  CAS  Google Scholar 

  3. Zakarija M, Garcia A, McKenzie JM. Studies on multiple thyroid cell membrane-directed antibodies in Graves’ disease. J Clin Invest 1985;76(5):1885–1891.

    Article  PubMed  CAS  Google Scholar 

  4. Arioglu E, Andewelt A, Diabo C, Bell M, Taylor SI, Gorden P. Clinical course of the syndrome of autoantibodies to the insulin receptor (type B insulin resistance): a 28-year perspective. Medicine 2002;81(2):87–100.

    Article  PubMed  CAS  Google Scholar 

  5. Braund WJ, Naylor BA, Williamson DH, et al. Autoimmunity to insulin receptor and hypoglycaemia in patient with Hodgkin’s disease. Lancet 1987;1(8527):237–240.

    Article  PubMed  CAS  Google Scholar 

  6. Chan JC, Zhu SQ, Ho SK, Cockram CS. Hypoglycaemia and Hodgkin’s disease. Br J Haematol 1990;76(3):434–436.

    Article  PubMed  CAS  Google Scholar 

  7. Khokher MA, Avasthy N, Taylor AM, Fonseca VA, Dandona P. Insulin-receptor antibody and hypoglycaemia associated with Hodgkin’s disease. Lancet 1987;1(8534):693–694.

    Article  PubMed  CAS  Google Scholar 

  8. Walters EG, Tavare JM, Denton RM, Walters G. Hypoglycaemia due to an insulin-receptor antibody in Hodgkin’s disease. Lancet 1987;1(8527):241–243.

    Article  PubMed  CAS  Google Scholar 

  9. Sluiter WJ, Marrink J, Houwen B. Monoclonal gammopathy with an insulin binding IgG(K) M-component, associated with severe hypoglycaemia. Br J Haematol 1986;62(4):679–687.

    Article  PubMed  CAS  Google Scholar 

  10. Wasada T, Eguchi Y, Takayama S, Yao K, Hirata Y, Ishii S. Insulin autoimmune syndrome associated with benign monoclonal gammopathy. Evidence for monoclonal insulin autoantibodies. Diabetes Care 1989;12(2):147–150.

    Article  PubMed  CAS  Google Scholar 

  11. Musso C, Javor E, Cochran E, Balow JE, Gorden P. Spectrum of renal diseases associated with extreme forms of insulin resistance. Clin J Am Soc Nephrol 2006;1(4):616–622.

    Article  PubMed  CAS  Google Scholar 

  12. Tsokos GC, Gorden P, Antonovych T, Wilson CB, Balow JE. Lupus nephritis and other autoimmune features in patients with diabetes mellitus due to autoantibody to insulin receptors. Ann Intern Med 1985;102(2):176–181.

    PubMed  CAS  Google Scholar 

  13. Varga J, Lopatin M, Boden G. Hypoglycemia due to antiinsulin receptor antibodies in systemic lupus erythematosus. J Rheumatol 1990;17(9):1226–1229.

    PubMed  CAS  Google Scholar 

  14. O’Brien TD, Rizza RA, Carney JA, Butler PC. Islet amyloidosis in a patient with chronic massive insulin resistance due to antiinsulin receptor antibodies. J Clin Endocrinol Metab 1994;79(1):290–292.

    Article  PubMed  Google Scholar 

  15. Archer JA, Gorden P, Roth J. Defect in insulin binding to receptors in obese man. Amelioration with calorie restriction. J Clin Invest 1975;55(1):166–174.

    Article  PubMed  CAS  Google Scholar 

  16. Kahn CR, Flier JS, Bar RS, et al. The syndromes of insulin resistance and acanthosis nigricans. Insulin-receptor disorders in man. N Engl J Med 1976;294(14):739–745.

    Article  PubMed  CAS  Google Scholar 

  17. Semple RK, Halberg NH, Burling K, et al. Paradoxical elevation of high-molecular weight adiponectin in acquired extreme insulin resistance due to insulin receptor antibodies. Diabetes 2007;56(6):1712–1717.

    Article  PubMed  CAS  Google Scholar 

  18. Semple RK, Soos MA, Luan J, et al. Elevated plasma adiponectin in humans with genetically defective insulin receptors. J Clin Endocrinol Metab 2006;91(8):3219–3223.

    Article  PubMed  CAS  Google Scholar 

  19. Flier JS, Kahn CR, Jarrett DB, Roth J. Characterization of antibodies to the insulin receptor: a cause of insulin-resistant diabetes in man. J Clin Invest 1976;58(6):1442–1449.

    Article  PubMed  CAS  Google Scholar 

  20. Flier JS, Kahn CR, Roth J, Bar RS. Antibodies that impair insulin receptor binding in an unusual diabetic syndrome with severe insulin resistance. Science 1975;190(4209):63–65.

    Article  PubMed  CAS  Google Scholar 

  21. Taylor SI, Underhill LH, Marcus-Samuels B. Assay of antibodies directed against cell surface receptors. Methods Enzymol 1985;109:656–667.

    Article  PubMed  CAS  Google Scholar 

  22. Bloise W, Wajchenberg BL, Moncada VY, Marcus-Samuels B, Taylor SI. Atypical antiinsulin receptor antibodies in a patient with type B insulin resistance and scleroderma. J Clin Endocrinol Metab 1989;68(1):227–231.

    Article  PubMed  CAS  Google Scholar 

  23. Boden G, Fujita-Yamaguchi Y, Shimoyama R, et al. Nonbinding inhibitory antiinsulin receptor antibodies. A new type of autoantibodies in human diabetes. J Clin Invest 1988;81(6):1971–1978.

    Article  PubMed  CAS  Google Scholar 

  24. Rodriguez O, Collier E, Arakaki R, Gorden P. Characterization of purified autoantibodies to the insulin receptor from six patients with type B insulin resistance. Metabolism 1992;41(3):325–331.

    Article  PubMed  CAS  Google Scholar 

  25. Kasuga M, Sasaki N, Kahn CR, Nissley SP, Rechler MM. Antireceptor antibodies as probes of insulinlike growth factor receptor structure. J Clin Invest 1983;72(4):1459–1469.

    Article  PubMed  CAS  Google Scholar 

  26. Zhang B, Roth RA. A region of the insulin receptor important for ligand binding (residues 450–601) is recognized by patients’ autoimmune antibodies and inhibitory monoclonal antibodies. Proc Natl Acad Sci U S A 1991;88(21):9858–9862.

    Article  PubMed  CAS  Google Scholar 

  27. Muggeo M, Kahn CR, Bar RS, Rechler M, Flier JS, Roth J. The underlying insulin receptor in patients with antireceptor autoantibodies: demonstration of normal binding and immunological properties. J Clin Endocrinol Metab 1979;49(1):110–119.

    Article  PubMed  CAS  Google Scholar 

  28. Taylor SI, 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;58(1):182–186.

    Article  PubMed  CAS  Google Scholar 

  29. Grunfeld C. Antibody against the insulin receptor causes disappearance of insulin receptors in 3T3-L1 cells: a possible explanation of antibody-induced insulin resistance. Proc Natl Acad Sci U S A 1984;81(8):2508–2511.

    Article  PubMed  CAS  Google Scholar 

  30. Shimoyama R, Shelmet JJ, Savage CR Jr, Boden G. Effects of anti-insulin receptor antibodies (AIRA) on downregulation and turnover of insulin receptors on cultured hepatocytes. Diabetes 1986;35(1):28–32.

    Article  PubMed  CAS  Google Scholar 

  31. Gorden P, Collier E, Roach P. Autoimmune mechanisms of insulin resistance and hypoglycemia. In: Moller DE, ed. Insulin Resistance. Chichester: John Wiley & Sons Ltd, 1993:123–142.

    Google Scholar 

  32. Coll AP, Morganstein D, Jayne D, Soos MA, O’Rahilly S, Burke J. Successful treatment of type B insulin resistance in a patient with otherwise quiescent systemic lupus erythematosus. Diabet Med 2005;22(6):814–815.

    Article  PubMed  CAS  Google Scholar 

  33. Zick Y, Rees-Jones RW, Taylor SI, Gorden P, Roth J. The role of antireceptor antibodies in stimulating phosphorylation of the insulin receptor. J Biol Chem 1984;259(7):4396–4400.

    PubMed  CAS  Google Scholar 

  34. Takayama-Hasumi S, Tobe K, Momomura K, et al. Autoantibodies to the insulin receptor (B-10) can stimulate tyrosine phosphorylation of the beta-subunit of the insulin receptor and a 185,000 molecular weight protein in rat hepatoma cells. J Clin Endocrinol Metab 1989;68(4):787–795.

    Article  PubMed  CAS  Google Scholar 

  35. Dons RF, Havlik R, Taylor SI, Baird KL, Chernick SS, Gorden P. Clinical disorders associated with autoantibodies to the insulin receptor. Simulation by passive transfer of immunoglobulins to rats. J Clin Invest 1983;72(3):1072–1080.

    Article  PubMed  CAS  Google Scholar 

  36. Kasuga M, Akanuma Y, Tsushima T, Suzuki K, Kosaka K, Kibata M. Effects of antiinsulin receptor autoantibody on the metabolism of rat adipocytes. J Clin Endocrinol Metab 1978;47(1):66–77.

    Article  PubMed  CAS  Google Scholar 

  37. Van Obberghen E, Spooner PM, Kahn CR, et al. Insulin-receptor antibodies mimic a late insulin effect. Nature 1979;280(5722):500–502.

    Article  PubMed  Google Scholar 

  38. Kasuga M, Akanuma Y, Tsushima T, et al. Effects of anti-insulin receptor autoantibodies on the metabolism of human adipocytes. Diabetes 1978;27(9):938–945.

    Article  PubMed  CAS  Google Scholar 

  39. Kahn CR, Baird KL, Flier JS, Jarrett DB. Effects of autoantibodies to the insulin receptor on isolated adipocytes. J Clin Invest 1977;60:1094–1106.

    Article  PubMed  CAS  Google Scholar 

  40. Kahn CR, Baird KL, Jarrett DB, Flier JS. Direct demonstration that receptor crosslinking or aggregation is important in insulin action. Proc Natl Acad Sci U S A 1978;75(9):4209–4213.

    Article  PubMed  CAS  Google Scholar 

  41. Grunfeld C, Jones DS, Shigenaga JK. Autoantibodies against the insulin receptor. Dissociation of the acute effects of the antibodies from the desensitization seen with prolonged exposure. Diabetes 1985;34(3):205–211.

    Article  PubMed  CAS  Google Scholar 

  42. Grunfeld C, Van Obberghen E, Karlsson FA, Kahn CR. Antibody-induced desensitization of the insulin receptor. Studies of the mechanism of desensitization in 3T3-L1 fatty fibroblasts. J Clin Invest 1980;66(5):1124–1134.

    Article  PubMed  CAS  Google Scholar 

  43. Taylor SI, Grunberger G, Marcus-Samuels B, et al. Hypoglycemia associated with antibodies to the insulin receptor. N Engl J Med 1982;307(23):1422–1426.

    Article  PubMed  CAS  Google Scholar 

  44. De Pirro R, Roth RA, Rossetti L, Goldfine ID. Characterization of the serum from a patient with insulin resistance and hypoglycemia. Evidence for multiple populations of insulin receptor antibodies with different receptor binding and insulin-mimicking activities. Diabetes 1984;33(3):301–304.

    Article  PubMed  Google Scholar 

  45. Tsushima T, Omori Y, Murakami H, Hirata Y, Shizume K. Demonstration of heterogeneity of autoantibodies to insulin receptors in type B insulin resistance by isoelectric focusing. Diabetes 1989;38(9):1090–1096.

    Article  PubMed  CAS  Google Scholar 

  46. Flier JS, Bar RS, Muggeo M, Kahn CR, Roth J, Gorden P. The evolving clinical course of patients with insulin receptor autoantibodies: spontaneous remission or receptor proliferation with hypoglycemia. J Clin Endocrinol Metab 1978;47(5):985–995.

    Article  PubMed  CAS  Google Scholar 

  47. Bao S, Root C, Jagasia S. Type B insulin resistance syndrome associated with systemic lupus erythematosus. Endocr Pract 2007;13(1):51–55.

    PubMed  Google Scholar 

  48. Eriksson JW, Bremell T, Eliasson B, Fowelin J, Fredriksson L, Yu ZW. Successful treatment with plasmapheresis, cyclophosphamide, and cyclosporin A in type B syndrome of insulin resistance. Case report. Diabetes Care 1998;21(8):1217–1220.

    Article  PubMed  CAS  Google Scholar 

  49. Fareau GG, Maldonado M, Oral E, Balasubramanyam A. Regression of acanthosis nigricans correlates with disappearance of anti-insulin receptor autoantibodies and achievement of euglycemia in type B insulin resistance syndrome. Metabolism 2007;56(5):670–675.

    Article  PubMed  CAS  Google Scholar 

  50. Freeland BS, Paglia RE, Seal DL. Clinical challenges of type B insulin resistance: a case study. Diabetes Educ 1998;24(6):728–733.

    Article  PubMed  CAS  Google Scholar 

  51. Gehi A, Webb A, Nolte M, Davis J Jr. Treatment of systemic lupus erythematosus-associated type B insulin resistance syndrome with cyclophosphamide and mycophenolate mofetil. Arthritis Rheum 2003;48(4):1067–1070.

    Article  PubMed  Google Scholar 

  52. Kato Y, Ichiki Y, Kitajima Y. A case of systemic lupus erythematosus presenting as hypoglycemia due to anti-insulin receptor antibodies. Rheumatol Int 2008;29(1):103–105.

    Article  PubMed  Google Scholar 

  53. Kawanishi K, Kawamura K, Nishina Y, Goto A, Okada S. Successful immunosuppressive therapy in insulin resistant diabetes caused by anti-insulin receptor autoantibodies. J Clin Endocrinol Metab 1977;44(1):15–21.

    Article  PubMed  CAS  Google Scholar 

  54. Kramer N, Rosenstein ED, Schneider G. Refractory hyperglycemia complicating an evolving connective tissue disease: response to cyclosporine. J Rheumatol 1998;25(4):816–818.

    PubMed  CAS  Google Scholar 

  55. Moller DE, Ratner RE, Borenstein DG, Taylor SI. Autoantibodies to the insulin receptor as a cause of autoimmune hypoglycemia in systemic lupus erythematosus. Am J Med 1988;84(2):334–338.

    Article  PubMed  CAS  Google Scholar 

  56. Muggeo M, Flier JS, Abrams RA, Harrison LC, Deisserroth AB, Kahn CR. Treatment by plasma exchange of a patient with autoantibodies to the insulin receptor. N Engl J Med 1979;300(9):477–480.

    Article  PubMed  CAS  Google Scholar 

  57. Nagayama Y, Morita H, Komukai D, Watanabe S, Yoshimura A. Type B insulin resistance syndrome induced by increased activity of systemic lupus erythematosus in a hemodialysis patient. Clin Nephrol 2008;69(2):130–134.

    PubMed  CAS  Google Scholar 

  58. Page KA, Dejardin S, Kahn CR, Kulkarni RN, Herold KC, Inzucchi SE. A patient with type B insulin resistance syndrome, responsive to immune therapy. Nat Clin Pract Endocrinol Metab 2007;3(12):835–840.

    Article  PubMed  Google Scholar 

  59. Rochet N, Blanche S, Carel JC, et al. Hypoglycaemia induced by antibodies to insulin receptor following a bone marrow transplantation in an immunodeficient child. Diabetologia 1989;32(3):167–172.

    Article  PubMed  CAS  Google Scholar 

  60. Selinger S, Tsai J, Pulini M, Saperstein A, Taylor S. Autoimmune thrombocytopenia and primary biliary cirrhosis with hypoglycemia and insulin receptor autoantibodies. A case report. Ann Intern Med 1987;107(5):686–688.

    PubMed  CAS  Google Scholar 

  61. Tardella L, Rossetti L, De Pirro R, et al. Circulating anti-insulin receptor antibodies in a patient suffering from lupus nephritis and hypoinsulinemic hypoglycaemia. J Clin Lab Immunol 1983;12(3):159–165.

    PubMed  CAS  Google Scholar 

  62. Toyota T, Suzuki H, Sugawara H, et al. Remission of insulin resistant diabetes in two patients with anti-insulin receptor antibodies. Tohoku J Exp Med 1982;138(2):187–197.

    Article  PubMed  CAS  Google Scholar 

  63. Vesely DL, Coleman MJ, Kohler PO, Jordan RM, Stanley S. Hyperalimentation as cause of markedly worsened metabolic control in a patient with autoantibodies to the insulin receptor. Am J Med 1985;79(4):504–508.

    Article  PubMed  CAS  Google Scholar 

  64. Sims RE, Rushford FE, Huston DP, Cunningham GR. Successful immunosuppressive therapy in a patient with autoantibodies to insulin receptors and immune complex glomerulonephritis. South Med J 1987;80(7):903–906.

    Article  PubMed  CAS  Google Scholar 

  65. Sato K, Okamura K, Yoshinari M, et al. Goitrous hypothyroidism with blocking or stimulating thyrotropin binding inhibitor immunoglobulins. J Clin Endocrinol Metab 1990;71(4):855–860.

    Article  PubMed  CAS  Google Scholar 

  66. Moncayo H, Moncayo R, Benz R, Wolf A, Lauritzen C. Ovarian failure and autoimmunity. Detection of autoantibodies directed against both the unoccupied luteinizing hormone/human chorionic gonadotropin receptor and the hormone-receptor complex of bovine corpus luteum. J Clin Invest 1989;84(6):1857–1865.

    Article  PubMed  CAS  Google Scholar 

  67. Sluss PM, Schneyer AL. Low molecular weight follicle-stimulating hormone receptor binding inhibitor in sera from premature ovarian failure patients. J Clin Endocrinol Metab 1992;74(6):1242–1246.

    Article  PubMed  CAS  Google Scholar 

  68. Larrick JW, Hyman ES. Acquired iron-deficiency anemia caused by an antibody against the transferrin receptor. N Engl J Med 1984;311(4):214–218.

    Article  PubMed  CAS  Google Scholar 

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  1. NIDDK/Clinical Endocrinology Branch, Clinical Research Center, National Institutes of Health, Bethesda, MD, USA

    Angeline Y. Chong & Phillip Gorden

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  1. Angeline Y. Chong
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  1. Health Sciences Center, Children's Hospital, University of Colorado, East 9th Avenue 4200, Denver, 80262, Colorado, USA

    George S. Eisenbarth

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Chong, A.Y., Gorden, P. (2011). Lessons from Patients with Anti-Insulin Receptor Autoantibodies. In: Eisenbarth, G. (eds) Immunoendocrinology: Scientific and Clinical Aspects. Contemporary Endocrinology. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-60327-478-4_22

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