Autoimmune Forms of Hypoglycemia

Autoimmune syndromes are a rare cause of hypoglycemia characterized by elevated levels of insulin in the presence of either anti-insulin antibodies (insulin autoimmune syndrome) or anti-insulin receptor antibodies (type B insulin resistance). Insulin autoimmune syndrome is the third leading cause of hypoglycemia in Japan, but has rarely been described in the non-Asian population. In the current study, we report the clinical and biochemical characteristics and clinical course of 2 white patients with insulin autoimmune syndrome, and present a literature review of non-Asian patients reported with insulin autoimmune syndrome. Also, we describe the clinical and biochemical characteristics of patients reported in the literature with type B insulin resistance who manifested hypoglycemia. We compare the clinical and laboratory features of insulin autoimmune syndrome and type B insulin resistance with each other and with other forms of hyperinsulinemic hypoglycemia. Autoimmune forms of hypoglycemia are uncommon. However, they should be considered in any patient with hypoglycemia in the setting of unsuppressed insulin levels associated with anti-insulin or anti-insulin receptor antibodies. Making the correct diagnosis may spare a hypoglycemic patient from an unnecessary pancreatic surgical procedure. Abbreviations: BMI = body mass index, CRC = Clinical Research Center, HLA = human leukocyte antigen, NIH = National Institutes of Health, SLE = systemic lupus erythematosus.

[1]  Y. Kitajima,et al.  A case of systemic lupus erythematosus presenting as hypoglycemia due to anti-insulin receptor antibodies , 2008, Rheumatology International.

[2]  K. Federlin,et al.  Rezidivierende Hypoglykämien bei Insulin-Autoimmunsyndrom , 2008 .

[3]  H. Morita,et al.  Type B insulin resistance syndrome induced by increased activity of systemic lupus erythematosus in a hemodialysis patient. , 2008, Clinical nephrology.

[4]  T. Kato,et al.  Severe hypoglycaemia in a person with insulin autoimmune syndrome accompanied by insulin receptor anomaly type B , 2007, Diabetic medicine : a journal of the British Diabetic Association.

[5]  S. Fineberg,et al.  Immunological responses to exogenous insulin. , 2007, Endocrine reviews.

[6]  D. Dunger,et al.  Paradoxical Elevation of High–Molecular Weight Adiponectin in Acquired Extreme Insulin Resistance Due to Insulin Receptor Antibodies , 2007, Diabetes.

[7]  S. O’Rahilly,et al.  Hypoglycemia due to an Insulin Binding Antibody in a Patient with an IgA-κ Myeloma , 2007 .

[8]  A. Balasubramanyam,et al.  Regression of acanthosis nigricans correlates with disappearance of anti-insulin receptor autoantibodies and achievement of euglycemia in type B insulin resistance syndrome. , 2007, Metabolism: clinical and experimental.

[9]  R. Reznek,et al.  Insulinomas may present with normoglycemia after prolonged fasting but glucose-stimulated hypoglycemia. , 2006, The Journal of clinical endocrinology and metabolism.

[10]  E. Van Obberghen,et al.  Spontaneous hypoglycaemia in the presence of both anti-insulin antibody and anti-insulin receptor antibody. , 2006, Diabetes & metabolism.

[11]  S. O’Rahilly,et al.  Elevated plasma adiponectin in humans with genetically defective insulin receptors. , 2006, The Journal of clinical endocrinology and metabolism.

[12]  J. Vieira,et al.  Insulin autoimmune syndrome (Hirata disease) as differential diagnosis in patients with hyperinsulinemic hypoglycemia. , 2006, Pancreas.

[13]  S. O’Rahilly,et al.  Successful treatment of Type B insulin resistance in a patient with otherwise quiescent systemic lupus erythematosus , 2005, Diabetic medicine : a journal of the British Diabetic Association.

[14]  A. Basu,et al.  Insulin autoimmunity and hypoglycemia in seven white patients. , 2005, Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists.

[15]  M. Vaisman,et al.  Insulin autoimmune syndrome: case report. , 2004, Sao Paulo medical journal = Revista paulista de medicina.

[16]  M. Reincke,et al.  Hypoglykämien und transienter Diabetes mellitus bei einem Autoimmun-Insulinsyndrom , 2004 .

[17]  M. Şahin,et al.  Autoimmune hypoglycemia in a type 2 diabetic patient with anti-insulin and insulin receptor antibodies. , 2004, Diabetes care.

[18]  S. Yaturu,et al.  Severe autoimmune hypoglycemia with insulin antibodies necessitating plasmapheresis. , 2004, Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists.

[19]  C. Chung,et al.  A case of autoimmune hypoglycemia complicated with diabetic ketoacidosis. , 2004, Yonsei medical journal.

[20]  J. Livesey,et al.  Insulin autoimmune syndrome due to IgG kappa paraprotein. , 2004, Pathology.

[21]  A. Gehi,et al.  Treatment of systemic lupus erythematosus-associated type B insulin resistance syndrome with cyclophosphamide and mycophenolate mofetil. , 2003, Arthritis and rheumatism.

[22]  G. Reach,et al.  [Insulin autoimmune syndrome revealing systemic lupus erythematosus]. , 2003, Annales de medecine interne.

[23]  M. Marazuela,et al.  Insulin autoimmune syndrome in a patient with viral hepatitis C , 2002, Clinical endocrinology.

[24]  Simeon I. Taylor,et al.  Clinical Course of the Syndrome of Autoantibodies to the Insulin Receptor (Type B Insulin Resistance): A 28-Year Perspective , 2002, Medicine.

[25]  L. Sobrinho,et al.  Hypoglycaemia due to insulin autoimmune syndrome: report of two cases with characterisation of HLA alleles and insulin autoantibodies. , 2001, European journal of endocrinology.

[26]  M. Vogeser,et al.  Autoimmune hypoglycemia presenting as seizure one week after surgery. , 2001, Clinical chemistry.

[27]  Y. Uchigata,et al.  Insulin autoimmune syndrome (IAS, Hirata disease). , 1999, Annales de medecine interne.

[28]  R. Rachmani,et al.  Insulin autoimmune syndrome after therapy with imipenem. , 1999, Diabetes care.

[29]  M. Maurí,et al.  Influence of Anti-Insulin Antibodies on Insulin Immunoassays in the Autoimmune Insulin Syndrome , 1998, Annals of clinical biochemistry.

[30]  B. Eliasson,et al.  Successful Treatment With Plasmapheresis, Cyclophosphamide, and Cyclosporin A in Type B Syndrome of Insulin Resistance: Case report , 1998, Diabetes Care.

[31]  B. Dinesen,et al.  [Autoimmune insulin syndrome. The first Danish case report]. , 1998, Ugeskrift for laeger.

[32]  F. Fazio,et al.  Imaging of the buffering effect of insulin antibodies in the autoimmune hypoglycemic syndrome. , 1998, The Journal of clinical endocrinology and metabolism.

[33]  A. Meinders,et al.  Recurrent hypoglycaemia caused by the insulin autoimmune syndrome: the first Dutch case. , 1996, The Netherlands journal of medicine.

[34]  P. Guggenbuhl,et al.  Autoimmune hypoglycemia occurring in tiopronin-treated rheumatoid arthritis. , 1996, Revue du rhumatisme.

[35]  L. Lumeng,et al.  Insulin autoimmune syndrome as a cause of spontaneous hypoglycemia in alcoholic cirrhosis. , 1995, Gastroenterology.

[36]  V. Tassi,et al.  Characterization of insulin autoantibodies in a patient with autoimmune hypoglycemia , 1995, Journal of endocrinological investigation.

[37]  R. Rizza,et al.  Islet amyloidosis in a patient with chronic massive insulin resistance due to antiinsulin receptor antibodies. , 1994, The Journal of clinical endocrinology and metabolism.

[38]  P. Halban,et al.  Hypoglycaemia caused by atypical insulin antibodies in a patient with benign monoclonal gammopathy , 1993, Journal of internal medicine.

[39]  C. Merlo,et al.  [Hypoglycemia and multiple myeloma]. , 1992, Schweizerische medizinische Wochenschrift.

[40]  G. Spinas,et al.  Insulin autoimmune syndrome and HLA-DR4 , 1992, The Lancet.

[41]  S. Clement,et al.  Reactive hypoglycemic coma due to insulin autoimmune syndrome: case report and literature review. , 1992, The American journal of medicine.

[42]  F. Nuttall,et al.  Hypoglycemia due to a monoclonal insulin-binding antibody in multiple myeloma. , 1992, The New England journal of medicine.

[43]  P. Gorden,et al.  Characterization of purified autoantibodies to the insulin receptor from six patients with type B insulin resistance. , 1992, Metabolism: clinical and experimental.

[44]  R. Roth,et al.  A region of the insulin receptor important for ligand binding (residues 450-601) is recognized by patients' autoimmune antibodies and inhibitory monoclonal antibodies. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[45]  S. Paolo,et al.  Insulin resistance and hypoglycemia in a patient with systemic lupus erythematosus: description of antiinsulin receptor antibodies that enhance insulin binding and inhibit insulin action. , 1991, The Journal of clinical endocrinology and metabolism.

[46]  J. Sodoyez,et al.  Polymorphism of insulin antibodies in six patients with insulin‐immune hypoglycaemic syndrome , 1991, Clinical and experimental immunology.

[47]  M. Lopatin,et al.  Hypoglycemia due to antiinsulin receptor antibodies in systemic lupus erythematosus. , 1990, The Journal of rheumatology.

[48]  A. Schneebaum,et al.  Systemic lupus erythematosus presenting as hypoglycemia with insulin receptor antibodies. , 1989, The Western journal of medicine.

[49]  Y. Omori,et al.  Demonstration of Heterogeneity of Autoantibodies to Insulin Receptors in Type B Insulin Resistance by Isoelectric Focusing , 1989, Diabetes.

[50]  H. Kiyokawa,et al.  Hyperinsulinemia due to impaired insulin clearance associated with fasting hypoglycemia and postprandial hyperglycemia: an analysis of a patient with antiinsulin receptor antibodies. , 1989, The Journal of clinical endocrinology and metabolism.

[51]  M. Kasuga,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. , 1989, The Journal of clinical endocrinology and metabolism.

[52]  A. Fischer,et al.  Hypoglycaemia induced by antibodies to insulin receptor following a bone marrow transplantation in an immunodeficient child , 1989, Diabetologia.

[53]  B. Laubie,et al.  [Autoimmune hypoglycemia: the fault of pyritinol?]. , 1988, Presse medicale.

[54]  C. Boitard,et al.  [Auto-immune hypoglycemic syndrome induced by pyritinol]. , 1988, Diabete & metabolisme.

[55]  G. Grunberger,et al.  Factitious hypoglycemia due to surreptitious administration of insulin. Diagnosis, treatment, and long-term follow-up. , 1988, Annals of internal medicine.

[56]  D. Moller,et al.  Autoantibodies to the insulin receptor as a cause of autoimmune hypoglycemia in systemic lupus erythematosus. , 1988, American Journal of Medicine.

[57]  S. Selinger,et al.  Autoimmune thrombocytopenia and primary biliary cirrhosis with hypoglycemia and insulin receptor autoantibodies. A case report. , 1987, Annals of internal medicine.

[58]  I. Cohen,et al.  Antibodies to Insulin Receptor Followed by Anti-Idiotype: Antibodies to Insulin in Child With Hypoglycemia , 1987, Diabetes.

[59]  P. Erb,et al.  Spontaneous Hypoglycemia Associated With Autoimmunity Specific to Human Insulin , 1987, Diabetes Care.

[60]  J. Tavaré,et al.  HYPOGLYCAEMIA DUE TO AN INSULIN-RECEPTOR ANTIBODY IN HODGKIN'S DISEASE , 1987, The Lancet.

[61]  R. Turner,et al.  AUTOIMMUNITY TO INSULIN RECEPTOR AND HYPOGLYCAEMIA IN PATIENT WITH HODGKIN'S DISEASE , 1987, The Lancet.

[62]  G. Benker,et al.  Clinical and biochemical aspects of the insulin autoimmune syndrome (IAIS) , 1986, Klinische Wochenschrift.

[63]  E A Benson,et al.  Insulin antibodies in patients receiving penicillamine. , 1985, The American journal of medicine.

[64]  E. A. Benson,et al.  Insulin autoimmunity as a cause of hypoglycemia. , 1984, Archives of internal medicine.

[65]  S. Taylor,et al.  The role of antireceptor antibodies in stimulating phosphorylation of the insulin receptor. , 1984, The Journal of biological chemistry.

[66]  R. Roth,et al.  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 , 1984, Diabetes.

[67]  R. Lauro,et al.  Circulating anti-insulin receptor antibodies in a patient suffering from lupus nephritis and hypoinsulinemic hypoglycaemia. , 1983, Journal of clinical & laboratory immunology.

[68]  S. Taylor,et al.  Clinical disorders associated with autoantibodies to the insulin receptor. Simulation by passive transfer of immunoglobulins to rats. , 1983, The Journal of clinical investigation.

[69]  P. Blackshear,et al.  Reactive hypoglycemia and insulin autoantibodies in drug-induced lupus erythematosus. , 1983, Annals of internal medicine.

[70]  G. Grunberger,et al.  Hypoglycemia associated with antibodies to the insulin receptor. , 1982, The New England journal of medicine.

[71]  H. Fujiya,et al.  Remission of insulin resistant diabetes in two patients with anti-insulin receptor antibodies. , 1982, The Tohoku journal of experimental medicine.

[72]  C. Kahn,et al.  Insulin-receptor antibodies mimic a late insulin effect , 1979, Nature.

[73]  W. Blackard,et al.  Characterization of circulating insulin and proinsulin-binding antibodies in autoimmune hypoglycemia. , 1979, The Journal of clinical investigation.

[74]  C. Kahn,et al.  The evolving clinical course of patients with insulin receptor autoantibodies: spontaneous remission or receptor proliferation with hypoglycemia. , 1978, The Journal of clinical endocrinology and metabolism.

[75]  M. Kasuga,et al.  Effects of Anti-insulin Receptor Autoantibodies on the Metabolism of Human Adipocytes , 1978, Diabetes.

[76]  M. Kasuga,et al.  Effects of antiinsulin receptor autoantibody on the metabolism of rat adipocytes. , 1978, The Journal of clinical endocrinology and metabolism.

[77]  C. Kahn,et al.  Effects of autoantibodies to the insulin receptor on isolated adipocytes. Studies of insulin binding and insulin action. , 1977, The Journal of clinical investigation.

[78]  C. Kahn,et al.  Characterization of antibodies to the insulin receptor: a cause of insulin-resistant diabetes in man. , 1976, The Journal of clinical investigation.

[79]  A. Frappier,et al.  B.C.G. vaccination and leukemia mortality. , 1970, Lancet.

[80]  Y. Uchigata The novel agent, alpha lipoic acid, can cause the development of insulin autoimmune syndrome. , 2007, Internal medicine.

[81]  S. O’Rahilly,et al.  Hypoglycemia due to an insulin binding antibody in a patient with an IgA-kappa myeloma. , 2007, The Journal of clinical endocrinology and metabolism.

[82]  E. Bognetti,et al.  An unusual case of recurrent hypoglycaemia: 10-year follow up of a child with insulin auto-immunity , 2005, European Journal of Pediatrics.

[83]  N. Reisch,et al.  [Hypoglycemia and transient diabetes mellitus in an insulin autoimmune syndrome]. , 2004, Deutsche medizinische Wochenschrift.

[84]  R. Paschke,et al.  Severe hypoglycemia due to insulin autoimmune syndrome with insulin autoantibodies crossreactive to proinsulin. , 2001, Experimental and clinical endocrinology & diabetes : official journal, German Society of Endocrinology [and] German Diabetes Association.

[85]  K. Eguchi,et al.  Anti-insulin receptor autoantibodies in a patient with type B insulin resistance and fasting hypoglycemia , 2000, Acta Diabetologica.

[86]  J. B. Redmon,et al.  Autoimmune hypoglycemia. , 1999, Endocrinology and metabolism clinics of North America.

[87]  P. Guillausseau,et al.  Insulin autoimmune syndrome: a rare cause of hypoglycaemia not to be overlooked. , 1999, Diabetes & metabolism.

[88]  J. Cresto,et al.  [Autoimmune hypoglycemia syndrome with specific anti-human insulin antibodies]. , 1996, Medicina.

[89]  Y. Omori,et al.  Insulin autoimmune syndrome (Hirata disease): clinical features and epidemiology in Japan. , 1994, Diabetes research and clinical practice.

[90]  L. Herranz,et al.  Autoimmune insulin syndrome in a patient with progressive systemic sclerosis receiving penicillamine. , 1992, Hormone research.

[91]  H. Velcovsky,et al.  [Recurrent hypoglycemia in the insulin autoimmune syndrome]. , 1990, Deutsche medizinische Wochenschrift.

[92]  B. Marcus-Samuels,et al.  Atypical antiinsulin receptor antibodies in a patient with type B insulin resistance and scleroderma. , 1989, The Journal of clinical endocrinology and metabolism.

[93]  G. Ville,et al.  [A French case of autoimmune hypoglycemia]. , 1988, Annales de medecine interne.

[94]  G. Cunningham,et al.  Successful immunosuppressive therapy in a patient with autoantibodies to insulin receptors and immune complex glomerulonephritis. , 1987, Southern medical journal.