Skip to main content
Log in

GAD, diabetes, and Stiff-Man syndrome: Some progress and more questions

  • Views
  • Facts, perspectives and opinions on selected topics
  • Published:
Journal of Endocrinological Investigation Aims and scope Submit manuscript

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

References

  1. Eisenbarth G.S. Type I diabetes mellitus: a chronic autoimmune disease. N. Engl. J. Med. 314: 1360, 1986.

    PubMed  CAS  Google Scholar 

  2. Bottazzo G.F., Florin-Christensen A., Doniach D. Islet cell antibodies in diabetes mellitus with autoimmune polyendocrine deficiencies. Lancet. 2: 1279, 1974.

    PubMed  CAS  Google Scholar 

  3. Palmer J., Asplin C.M., Clemons P., Lyen K., Tatputi O., Raghu P.K., Pasguette T.L. Insulin antibodies in insulin-dependent diabetes before insulin treatment. Science. 222: 1337, 1983.

    PubMed  CAS  Google Scholar 

  4. Solimena M., Folli F., Aparisi R., Pozza G., De Camilli P. Autoantibodies to GABAergic neurons and pancreatic ß-cells in Stiff-Man syndrome. N. Engl. J. Med. 322: 1555, 1990.

    PubMed  CAS  Google Scholar 

  5. Bækkeskov S., Aanstoot H.J., Christgau S., Reetz A., Solimena M., Cascalho M., Folli F., Richter-Olesen H., De Camilli P. Identification of the 64 Kd autoantigen in insulin-dependent diabetes mellitus as the GABA-synthesizing enzyme glutamic acid decarboxylase. Nature. 347: 151, 1990.

    PubMed  Google Scholar 

  6. Bækkeskov S., Nielsen J., Nielsen J.H., Marner B.T., Bilde J., Ludvigsson, Lernmark A. Autoantibodies in newly diagnosed diabetic children immunoprecipitate human pancreatic islet cell proteins. Nature 298: 167, 1982.

    PubMed  Google Scholar 

  7. Castano L., Russo E., Zhou L., Lipes M.A., Eisenbarth G. Identification and cloning of a granule autoantigen (Carboxypeptidase-H) associated with type I diabetes. J. Clin. Endocrinol. Metab. 73: 1197, 1991.

    PubMed  CAS  Google Scholar 

  8. Karjalainen J., Martin J., Knip M., Ilonen J., Robinson B.H., Avilahti E., Akerblom H.K., Dosch H.M. A bovine albumin peptide as a possible trigger of insulin-dependent diabetes mellitus. N. Engl. J. Med. 327: 302, 1992.

    PubMed  CAS  Google Scholar 

  9. Pietropaolo M., Castano L., Babu S., Buelow R., Kuo Y-L.S., Martin S., Martin A., Powers A.C., Prochazka M., Naggert J., Leiter J.H., Eisenbarth G.S. Islet cell autoantigen 69kDa (ICA69): molecular cloning and characterization of a novel diabetes associated autoantigen. J. Clin. Invest. 92: 359, 1993.

    PubMed Central  PubMed  CAS  Google Scholar 

  10. Nayak R.C., Omar M.A.K., Rabizadeh A., Srikanta S., Eisenbarth G.S. “Cytoplasmic” islet cell antibodies: evidence that the target antigen is a sialogycogonjugate. Diabetes. 34: 617, 1985.

    PubMed  CAS  Google Scholar 

  11. Dotta F., Ziegler R., O’Neill J., Nayak R., Eisenbarth G.S., Appel M. Islet autoimmunity identification and initial characterization of metabolically regulatable pancreatic gangliosides. Diabetologia. 19: 483a (Abstract), 1989.

    Google Scholar 

  12. Elias D., Markovits D., Reshef T., van der Zee R., Cohen I.R. Induction and therapy of autoimmune diabetes in the non-obese diabetic mouse by a 65-kDa heat shock protein. Proc. Natl. Acad. Sci. USA. 87: 1567, 1990.

    Google Scholar 

  13. Elias D., Reshef T., Birk O., van der Zee R., Walker M.D., Cohen I.R. Vaccination against autoimmune mouse diabetes with a T-cell epitope of the human 65-kDa heat shock protein. Proc. Natl. Acad. Sci. USA. 88: 3088, 1991.

    PubMed Central  PubMed  CAS  Google Scholar 

  14. Kampe O., Velloso L., Andersson A., Karlsson A. No role for 65-kDa heat-shock protein in diabetes. Lancet. 336: 1250, 1990.

    Google Scholar 

  15. Atkinson M.A., Holmes L.A. Sharp D.W., Lacy P.E., Maclaren N.K. No evidence for serological autoimmunity toward islet cell heat shock protein in insulin-dependent diabetes. J. Clin. Invest. 7: 721, 1991.

    Google Scholar 

  16. Roep B.O., Ardent S.D., de Vries R.R.P., Hutton J.C. T-cell clones from a type-1 diabetes patient respond to insulin secretory granule proteins. Nature. 345: 632, 1990.

    PubMed  CAS  Google Scholar 

  17. Roep B.O., Kallan A.A., Hazenbos W.L.W., Bruining G.J., Baileys E.M. Ardern S.D., Hutton J.C., de Vries R.R.P. T cell reactivity to 38kD insulin-secretory-granule protein in patients with recent-onset type I diabetes Lancet. 337: 1439, 1991.

    PubMed  CAS  Google Scholar 

  18. Sutherland D.E., Sibley R., Xu X.Z., Michael A., Srikanta A.M., Taub F., Najarian J., Goetz F.C. Twin to twin pancreas transplatation: reversal and reenactment of the pathogenesis of type I diabetes Trans. Assc. Am. Phys. 97: 80, 1984.

    CAS  Google Scholar 

  19. Miller B.J., Apple M.C., O’Neil J.J., Wicker L.S. Both the Lyt-2+ and L3T4+ T-cell subsets are required for the transfer of diabetes in non-obese diabetic mice. J. Immunol. 140: 52, 1988.

    PubMed  CAS  Google Scholar 

  20. Hayward A.R., Cobbold S.P., Waldman H., Cooke A., Simpson E. Delay in onset of insulitis in NOD mice following a single injection of CD4 and CD8 antibodies. J. Autoimmun. 1: 91, 1988.

    PubMed  CAS  Google Scholar 

  21. Reich E.P., Sherwin R.S., Kanagawa O., Janeway C.A.J. An explanation for the protective effect of MHC class II I-E molecule in murine diabetes. Nature. 341: 326, 1989.

    PubMed  CAS  Google Scholar 

  22. Kaufman D.L., Clare-Salzer M., Tian J., Forsthuber T., Ting G.S.P., Robinson P., Atkinson M.A., Sercarz E.E., Tobin A.J., Lehmann P.V. Spontaneous loss of T-cell tolerance to glutamic acid decarboxylase in murine insulin-dependent diabetes. Nature. 366: 69, 1993.

    PubMed  CAS  Google Scholar 

  23. Tisch R., Yang X.-D., Singer S.M., Liblau R.S., Fugger L., McDevitt H.O. Immune response to glutamic acid decarboxylase correlates with insulitis in non-obese diabetic mice. Nature. 366: 72, 1993.

    PubMed  CAS  Google Scholar 

  24. Roberts E., Frankel S. Further studies of glutamic acid decarboxylase in brain. J. Biol.Chem. 188: 789, 1951.

    PubMed  CAS  Google Scholar 

  25. Erlander M.G., Tobin A.J. The structural and functional heterogeneity of glutamic acid decarboxylase: a review. Neurochem. Res. 16: 215, 1991.

    PubMed  CAS  Google Scholar 

  26. Karlsen A.E., Hagopian W.A., Grubin C.E., Dube S., Disteche C.M., Adler D.A., Barmeier H., Mathewes S., Grant F.J., Foster D., Lernmark A. Cloning and primary structure of a human islet isoform of glutamic acid decarboxylase from chromosome 10. Proc. Natl. Acad. Sci. USA. 88: 8337, 1991.

    PubMed Central  PubMed  CAS  Google Scholar 

  27. Bu D.-F., Erlander M.G., Hitz B.C., Tillakaratne N.J.K., Kaufman D.L., Wagner-McPherson C.B., Evans G.A., Tobin A.J. Two human glutamate decarboxylases 65-kDa GAD and 67-kDa GAD are each encoded by a single gene. Proc. Natl. Acad. Sci. USA. 89: 2115, 1992.

    PubMed Central  PubMed  CAS  Google Scholar 

  28. Wyborski R.J., Bond R.W., Gottlieb D.I. Characterization of a cDNA coding for rat glutamic acid decarboxylase. Molecular Brain Research. 8: 193, 1990.

    PubMed  CAS  Google Scholar 

  29. Julien J.F., Samama P., Mallet J. Rat brain glutamic acid decarboxylase sequence deduced from a cloned cDNA. J. Neurochem. 54: 703, 1990.

    PubMed  CAS  Google Scholar 

  30. Erlander M.G., Tillakaratne N.J.K., Feldblum S., Patel N., Tobin A.J. Two genes encode distinct glutamate decarboxylases. Neuron 7: 91, 1991.

    PubMed  CAS  Google Scholar 

  31. Michelsen B.K., Petersen J.S., Boel E., Møldrup A., Dyrberg T., Madsen O.D. Cloning characterization and autoimmune recognition of rat islet glutamic acid decarboxylase in insulin-dependent diabetes mellitus. Proc. Natl. Acad. Sci. USA. 88: 8754, 1991.

    PubMed Central  PubMed  CAS  Google Scholar 

  32. Katarova Z., Szabo G., Mugnaini E., Greenspan R.J. Molecular identification of the 62 kd form of glutamic acid decarboxylase from the mouse. European J. Neuroscience. 2: 190, 1990.

    Google Scholar 

  33. Lee D.S., Tian J., Phan T., Kaufman D.L. Cloning and sequence analysis of a murine cDNA encoding glutamate decarboxylase (GAD65). Biochem. Biophys. Acta. 1216: 157, 1993.

    PubMed  CAS  Google Scholar 

  34. Kobayashi Y., Kaufman D.L., Tobin A.J. Glutamic acid decarboxylase cDNA: nucleotide sequence encoding and enzymatically active fusion protein. J. Neurosci. 7: 2768, 1987.

    PubMed  CAS  Google Scholar 

  35. Jackson F.R., Newby L.M., Kulkarni S.J. Drosophila GABAergic systems: sequence and expression of glutamic acid decarboxylase. J. Neurochem. 54: 1068, 1990.

    PubMed  CAS  Google Scholar 

  36. Christgau S., Aanstoot H.-J., Schierbeck H., Begley K., Tullin S., Hejnaes K., Bækkeskov S. Membrane anchoring of the autoantigen GAD65 to microvesicles in pancreatic ß-cells by palmitoylation in the NH2-terminal domain. J. Cell. Biol. 118: 309, 1992.

    PubMed  CAS  Google Scholar 

  37. Solimena M., Aggujaro D., Muntzel C., Dirkx R., Butler M., De Camilli P., Hayday A. Association of GAD-65 but not of GAD-67 with the Golgi complex of transfected Chinese hamster ovary cells mediated by the N-terminal region. Proc. Natl. Acad. Sci. USA. 90: 3073, 1993.

    PubMed Central  PubMed  CAS  Google Scholar 

  38. Shi Y., Veit B., Bækkeskov S. Amino acid residues 24–31 but not palmitoylation of cysteins 30 and 45 are required for membrane anchoring of glutamic acid decarboxylase GAD65. J. Cell. Biol. 124: 927, 1994.

    PubMed  CAS  Google Scholar 

  39. Solimena M., Dirkx R., Radzynski M., Mundigl O., De Camilli P. A signal located within amino acids 1–27 of GAD65 is required for its targeting to the Golgi complex region. J. Cell Biol. In press, 1994.

  40. Brilliant M.H., Szabo G., Katarova Z., Kozak C.A., Glaser T.M., Greenspan R.J., Housman D.E. Sequences homologous to glutamic acid decarboxylase cDNA are present on mouse chromosomes 2 and 10. Genomics. 6: 115, 1990.

    PubMed  CAS  Google Scholar 

  41. Edelhoff S., Grubin C.E., Karlsen A.E., Alder D.A., Foster D., Disteche C.M., Lernmark A. Mapping of glutamic acid decarboxylase (GAD) genes. Genomics 17: 93, 1993.

    PubMed  CAS  Google Scholar 

  42. Maras B, Sweeney G, Barra D., Bossa F, John RA. The amino acid sequence of glutamate decarboxylase from Escherichia coli. Evolutionary relationship between mammalian and bacterial enzymes: Eur. J. Biochem. 204: 93, 1992.

    PubMed  CAS  Google Scholar 

  43. Baum G., Chen Y., Arazi T., Takatsuji H., Fromm H. A plant glutamate decarboxylase containing a calmodulin binding domain. Cloning sequence and functional analysis. J. Biol. Chem. 268: 19610, 1993.

    CAS  Google Scholar 

  44. Martin D.L. Regulatory properties of brain glutamate decarboxylase. Cell. Mol. Neurobiol. 7: 237, 1987.

    PubMed  CAS  Google Scholar 

  45. Kaufman D.L., Houser C.R., Tobin A.J. Two forms of the GABA synthetic enzyme glutamate decarboxylase have distinct intraneuronal distributions and cofactor interactions. J. Neurochem. 56: 720, 1991.

    PubMed  CAS  Google Scholar 

  46. Martin D.L., Martin S.B., Wu S.J., Espina N. Cofactor interactions and the regulation of glutamate decarboxylase activity. Neurochem. Res. 16: 243, 1991a.

    PubMed  CAS  Google Scholar 

  47. Martin D.L., Martin S.B., Wu S.J., Espina N. Regulatory properties of brain glutamate decarboxylase (GAD): the apoenzyme of GAD is present principally as the smaller of two molecular forms of GAD in brain. J. Neurosci. 11: 2725, 1991b.

    PubMed  CAS  Google Scholar 

  48. Mugnaini E., Oertel W.H. An atlas of the distribution of GABAergic neurons and terminals in the rat CNS as revealed by GAD immunohistochemistry. In: Handbook of Chemical Neuroanatomy Vol. 4: GABA and Neuropeptides in the CNS Part I. A. Bjorklund and T. Hökfelt, editors. Elsevier Science Publishers B.V. Amsterdam. 436, 1985.

  49. Esclapez M., Tillakaratne N.J.K., Kaufman D.L., Tobin A.J., Houser C.R. Comparative localization of two forms of glutamic acid decarboxylase and their mRNA in rat brain support the concepts of functional differences between the forms. J. Neurosci. 14: 1834, 1994.

    PubMed  CAS  Google Scholar 

  50. Vincent S.R., Hökfelt T., Wu J.-Y., Elde R.P., Morgan L.M., Kimmel J.R. Immunohistochemical studies of the GABA system in the pancreas. Neuroendocrin. 36: 197, 1983.

    CAS  Google Scholar 

  51. Okada Y. In: GABAergic Mechanisms in the Mammalian Periphery. S.L. Erdo and N.G. Bower editors. Raven Press New York. 223, 1986.

  52. Garry D.J., Garry M.G., Sorenson R.L. Ultrastructural immunocytochemical localization of L-glutamate decarboxylase and GABA in rat pancreatic zymogen granules. Cell Tssue Res. 252: 191, 1988.

    CAS  Google Scholar 

  53. Reetz A., Solimena M., Matteoli M., Folli F., Takei K., De Camilli P. GABA and pancreatic ß-cells: colocalization of glutamic acid decarboxylase (GAD) and GABA with synaptic-like microvesicles suggests their role in GABA storage and secretion. EMBO J. 10: 1275, 1991.

    PubMed Central  PubMed  CAS  Google Scholar 

  54. Erdo S.L., Joo F., Wolff J.F. Immunohistochemical localization of glutamate decarboxylase in the rat oviduct and ovary: further evidence for non-neuronal GABA system. Cell Tissue Res. 255: 431, 1990.

    Google Scholar 

  55. Tillakaratne N.J.K., Erlander M.G., Collard M.W., Greif K.F., Tobin A.J. Glutamate decarboxylases in nonneuronal cells of rat testis and oviduct: differential expression of GAD65 and GAD67. J. Neurochem. 58: 618, 1992.

    PubMed  CAS  Google Scholar 

  56. Persson H., Pelto-Huikko M., Metsis M., Soder O., Brene S., Skog S., Hökfelt T., Ritzen E.M. Expression of the neurotransmitter-synthesizing enzyme glutamic acid decarboxylase in male germ cells Mol. Cell. Biol. 10: 4701, 1990.

    CAS  Google Scholar 

  57. Faulkner-Jones B.E., Cram D.S., Kun J., Harrison L.C. Localization and quantitation of expression of two glutamate decarboxylase genes in pancreatic ß-cells and other peripheral tissues of mouse and rat. Endocrinol. 133: 2962, 1993.

    CAS  Google Scholar 

  58. Petersen J.S., Russel S., Marshall M.O., Kofod H., Buschard K., Cambon N., Karlsen A.E., Boel E., Hagopian W.A., Hejnaes K.R., Moody A., Dyrberg T., Lernmark Å., Madsen O.D., Michelsen B.K. Differential expression of glutamic acid decarboxylase in rat and human islets. Diabetes. 42: 484, 1993.

    PubMed  CAS  Google Scholar 

  59. Velloso L.A., Kampe O., Eizirik D.L., Hallberg A., Andersson A., Karlsson F.A. Human autoantibodies react with glutamic acid decarboxylase antigen in human and rat but not in mouse pancreatic islets. Diabetologia. 36: 39, 1993a.

    PubMed  CAS  Google Scholar 

  60. Kim J., Richter W., Aanstoot H.-J., Shi Y., Fu Q., Rajotte R., Warnock G., Bækkeskov S. Differential expression of GAD65 and GAD67 in human rat and mouse pancreatic islets. Diabetes. 42: 1799, 1993.

    PubMed  CAS  Google Scholar 

  61. Chang Y.-C., Gottlieb D.I. Characterization of the proteins purified with monoclonal antibodies to glutamic acid decarboxylase. J. Neurosci. 8: 2123, 1988.

    PubMed  CAS  Google Scholar 

  62. De Camilli P., Jahn R. Pathways to regulated exocytosis in neurons. Ann. Rev. Physiol. 52: 625, 1990.

    Google Scholar 

  63. Maycox P.R., Hell J.W., Jahn R. Amino acid neurotransmission: spotlight on synaptic vesicles. Trends Neurosci. 13: 83, 1990.

    PubMed  CAS  Google Scholar 

  64. Sorenson R.L., Garry D.G., Brelje T.C. Structural and functional considerations of GABA in islets of Langerhans ß-cells and nerves. Diabetes. 41: 1365, 1991.

    Google Scholar 

  65. Ahner-Hilger G., Widenmann B. The amphicrine pancreatic cell line AR42J secretes GABA and amylase by seperate regulated pathways. FEBS Lett. 314: 41, 1992.

    Google Scholar 

  66. Thomas-Reetz A., Hell J.W., During M.J., Walch-Solimena C., Jahn R., De Camilli P. A γ-aminobutyric acid transporter driven by a proton pump is present in synaptic-like microvesicles of pancreatic ß cells. Proc. Natl. Acad. Sci. USA 90: 5317, 1993.

    PubMed Central  PubMed  CAS  Google Scholar 

  67. Thomas-Reetz A., De Camilli P. A role for synaptic vesicles in non-neuronal cells: clues from pancreatic ß-cells and from chromaffin cells. Faseb. J. 8: 209, 1994.

    PubMed  CAS  Google Scholar 

  68. Christgau S, Schierbeck H, Aanstoot H-J, Aagard L., Begley K, Kofod H, Hejnes K, Bækkeskov S. Pancreatic ß-cells express two autoantigenic forms of glutamic acid decarboxylase a 65kDa hydrophilic form and a 64kDa amphiphilic form which can be both membrane-bound and soluble. J. Biol. Chem. 266: 21254, 1991.

    Google Scholar 

  69. Solimena M., Folli F., Denis-Donini S., Comi G.C., Pozza G., De Camilli P., Vicari A.M. Autoantibodies to glutamic acid decarboxylase in a patient with Stiff-Man syndrome epilepsy and type I diabetes mellitus. N. Engl. J. Med. 318: 1012, 1988.

    PubMed  CAS  Google Scholar 

  70. Moersch F.P., Woltman H.W. Progressive and fluctuating muscular rigidity and spasm (stiff-man syndrome): report of a case and some observation in 13 other cases. Mayo Clin. Proc. 31: 421, 1956.

    CAS  Google Scholar 

  71. Blum P., Jankovic J. Stiff-Person syndrome: an autoimmune disease. Movement Dis. 6: 12, 1991.

    PubMed  CAS  Google Scholar 

  72. McEvoy K.M. Stiff-Man syndrome. Mayo Clinic. Proc. 66: 300, 1991.

    CAS  Google Scholar 

  73. Meinck H.M., Ricker K., Hulser P.J., Schmid E., Pfeiffer J., Solimena M. Stiff-Man syndrome: clinical and laboratory findings in eight patients. J. Neurol. 241: 157, 1994.

    PubMed  CAS  Google Scholar 

  74. Meinck H.M., Ricker K., Conrad B. The Stiff-Man syndrome: new pathophysiological aspects from abnormal exteroceptive reflexes and ther response to clorimipramine clonidine and tizanidine. J. Neurol. Neurosurg. Psychiatry 47: 280, 1984.

    PubMed Central  PubMed  CAS  Google Scholar 

  75. Lorish T.R., Thorsteinsson G., Howard Jr., F.M. Stiff-man syndrome updated. Mayo Clin. Proc. 64: 629–636, 1989.

    PubMed  CAS  Google Scholar 

  76. Solimena M., De Camilli P. Autoimmunity to glutamic acid decarboxylase (GAD) in Stiff-Man syndrome and insulin-dependent diabetes mellitus. TINS. 14: 452, 1991.

    PubMed  CAS  Google Scholar 

  77. Gorin F., Baldwin B., Tait R., Pathak R., Seyal M., Mugnaini E. Stiff-man syndrome: a GABAergic autoimmune disorder with autoantigenic heterogeneity. Ann Neurol. 28: 71, 1990.

    Google Scholar 

  78. Young W. The Stiff-man syndrome. Br. J. Clic. Pract. 20: 507, 1966.

    CAS  Google Scholar 

  79. Martinelli P., Montagna P. Exteroceptive reflexes abnormalities in stiff-man syndrome. J. Neurol. Neurosurg. Psychiatry 48: 92, 1985.

    PubMed Central  PubMed  CAS  Google Scholar 

  80. Meldrum B.S. Anatomy physiology and pathology of epilepsy. Lancet 336: 231, 1990.

    PubMed  CAS  Google Scholar 

  81. Butler M., Solimena M., Dirkx R., Hayday A., De Camilli P. Identification of a dominant epitope of glutamic acid decarboxylase (GAD65) recognized by autoanti-bodies in Stiff-Man syndrome. J. Exp. Med. 178: 2097, 1993.

    PubMed  CAS  Google Scholar 

  82. Vicari A., Folli F., Pozza G., Comi G.C., Comola M., Canal N., Besana C., Borri A., Tresoldi M., Solimena M., De Camilli P. Plasmapheresis in the treatment of Stiff-Man syndrome. New Engl. J. Med. 320: 1499, 1989.

    PubMed  CAS  Google Scholar 

  83. Harding A.E., Thompson P.D., Kocen R.S., Batchelor J.R., Davey N., Marsden C.D. Plasma exchange and immunosuppression in Stiffman syndrome. Lancet 2: 915, 1989.

    PubMed  CAS  Google Scholar 

  84. Brashear H.R., Phillips L.H. Autoantibodies to GABA-ergic neurons and response to plasmapheresis in stiff-man syndrome. Neurology 41: 1588, 1992.

    Google Scholar 

  85. George T.M., Burke J.M., Sobotka P.A., Greenberg H.S., Vinik I. Resolution of Stiff-man syndrome with cortisol replacement in a patient with deficiences of ACTH growth hormone and prolactin. N. Engl. J. Med. 310: 1511, 1984.

    PubMed  CAS  Google Scholar 

  86. Piccolo G., Cosi V. Stiff-man syndrome dysimmune disorder and cancer. Ann. Neurol. 26: 205, 1989.

    Google Scholar 

  87. McEvoy K.M., Ahslskog J.E. Antibody-positive stiff-man syndrome responding to immunosuppression. Neurology 41: 143, 1991.

    Google Scholar 

  88. Gianani R., Pugliese A., Bonner-Weir S., Shiffrin A.J., Soeldner J.S., Erlich H., Awdeh Z., Alper C.A., Jackson R.A., Eisenbarth G.S. Prognostically significant heterogeneity of cytoplasmic islet cell autoantibodies in relatives of patients with type I diabetes. Diabetes. 41: 347, 1992.

    PubMed  CAS  Google Scholar 

  89. Atkinson M.A., Kaufman D.L., Campbell L., Tobin A.J., Maclaren N.K. Islet cells cytoplasmic autoantibody reactivity to glutamate decarboxylase in insulin-dependent diabetes. J. Clin. Invest. 91: 350, 1993.

    PubMed Central  PubMed  CAS  Google Scholar 

  90. Gianani R., Pugliese A., Verge C., Moromisato R., Yamada K., Butler M., Solimena M., De Camilli P., Erlich H., Jackson R., Eisenbarth G.S. Characterization of three subsets of ICA: restricted (mouse negative human and rat positive GAD absorbable); non-restricted (human mouse rat positive and not GAD absorbable) and human specific (human specific not GAD absorbable). Diabetes (submitted).

  91. Williams A.C., Nutt J.G., Hare T. Autoimmunity in Stiff-man syndrome. Lancet 2: 222, 1988.

    PubMed  CAS  Google Scholar 

  92. Pugliese A., Solimena M., Awdeh Z.L., Alper C.A., Bugawan T., Erlich H.A., De Camilli P., Eisenbarth G.S. Association of HLA-DQB1*0201 with Stiff-Man syndrome. J. Clin. Endocrinol. Metab. 1550, 1993.

  93. Baisch J.M., Weeks T., Giles R., Hoover M., Stastny P., Capra J.D. Analysis of HLA-DQ genotypes and susceptibility in insulin-dependent diabetes mellitus. N. Engl. J. Med. 322: 1836, 1990.

    PubMed  CAS  Google Scholar 

  94. Caillat-Zucman S., Garchon H.J., Timsit J., Assan R., Boitard C., Djilali-Saiah I., Bougneres P., Bach J.F. Age dependent HLA genetic heterogeneity of type I insulin-dependent diabetes mellitus. J. Clin. Invest. 90: 2242, 1992.

    PubMed Central  PubMed  CAS  Google Scholar 

  95. Bækkeskov S., Landin M., Kristensen J., Srikanta S., Bruining G., Mandrup-Poulsen T., de Beaufort C., Soeldner J., Eisenbarth G.S., Lindgren F., Sundquist G., Lernmark Å. Antibodies to a 64000 M human islet cell antigen precede the clinical onset of insulin-dependent diabetes. J. Clin. Invest. 79: 926, 1987.

    PubMed Central  PubMed  Google Scholar 

  96. Atkinson M.A., Maclaren N.K., Scharp D.W., Lacey P.E., Riley W.J. 64000 Mr autoantibodies as predictors of insulin-dependent diabetes mellitus. Lancet. 335: 1357, 1990.

    PubMed  CAS  Google Scholar 

  97. Hagopian W.A., Karlson A.E., Gottsater A., Landin-Olsson M., Grubin C.E., Sundkvist G., Petersen J.S., Boel E., Cyrberg T., Lernmark Å. Quantitative assay using recombinant human islet glutamic acid decarboxylase (GAD65) shows that 64K autoantibody positivity at onset predicts diabetes type. J. Clin. Invest. 91: 368, 1993.

    PubMed Central  PubMed  CAS  Google Scholar 

  98. Rowley M.J., MacKay R., Chen Q., Knowles W.J., Zimmet P.Z. Autoantibodies to glutamic acid decarboxylase discriminate major types of diabetes mellitus. Diabetes 41: 548, 1992.

    PubMed  CAS  Google Scholar 

  99. Bækkeskov S., Dyrberg T., Lernmark Å. Autoantibodies to a 64-kilodalton islet cell protein precede the onset of spontaneous diabetes in the BB rat. Science. 224: 1348, 1984.

    PubMed  Google Scholar 

  100. Karlsen A.E., Hagopian WA, Petersen J.S., Boel E., Dyrberg T., Grubin C.E., Michelsen B.K., Madsen O.D., Lernmark Å. Recombinant glutamic acid decarboxylase (representing the single isoform expressed in human islets) detects IDDM-associated 64000-M(r) autoantibodies. Diabetes. 41: 1355, 1992.

    PubMed  CAS  Google Scholar 

  101. Richter W., Eiermann T.H., Endl J., Seissler J., Wolfhart S., Brandt M., Jungfer H., Scherbaum W.A. Human monoclonal islet specific autoantibodies share features of islet cell and 64 kDa antibodies. Diabetologia 36: 785–790, 1992.

    Google Scholar 

  102. Richter W., Shi Y., Bækkeskov S. Autoreactive epitopes defined by diabetes-association human monoclonal antibodies are localizaed in the middle and C-terminal domains of the smaller form of glutamate decarboxylase. Proc. Natl. Acad. Sci. USA 90: 2832, 1993.

    PubMed Central  PubMed  CAS  Google Scholar 

  103. Velloso L.A., Kampe O., Hallberg A., Christmanson L., Betsholtz C., Karlsson F.A. Demonstration of GAD-65 as the main immunogenic isoform of glutamate decarboxylase in type 1 diabetes and determination of autoantibodies using a radioligand produced by eukaryotic expression. J. Clin. Invest. 91: 2084, 1993.

    PubMed Central  PubMed  CAS  Google Scholar 

  104. Kaufman D.L., Erlander M.G., Claire-Salzler M., Atkinson MA, Maclaren N.K., Tobin A.J. Autoimmunity to two forms of glutamate decarboxylase in insulin dependent diabetes mellitus. J. Clin. Invest. 89: 283, 1992.

    PubMed Central  PubMed  CAS  Google Scholar 

  105. Mauch L., Seissler J., Haubruck H., Cook N.J., Abney C.C., Berthold H., Wirbelauer C., Liedvogel B., Scherbaum W.A., Northemann W. Baculovirus-mediated expression of human 65 kDa and 67 kDa glutamic acid decarboxylases in SF9 insect cells and their relevance in diagnosis of insulin-dependent diabetes mellitus. J. Biochem. 113: 699, 1993.

    PubMed  CAS  Google Scholar 

  106. DeAizpurua H.J., Harrison L.C., Cram D.S. An ELISA for antibodies to recombinant glutamic acid decarboxylase in IDDM. Diabetes 41: 1182, 1992.

    PubMed  CAS  Google Scholar 

  107. Martino G.V., Tappaz M.L., Braghi S., Dozio N., Canal N., Pozza G., Bottazzo G.F., Grimaldi L.M., Bosi E. Autoantibodies to glutamic acid decarboxylase (GAD) detected by an immuno-trapping enzyme activity assay: relation to insulin-dependent diabetes mellitus and islet cell antibodies. J. Autoimm. 4: 915, 1991.

    CAS  Google Scholar 

  108. Christie M.R., Brown T.J., Cassidy D. Binding of antibodies in sera from type 1 (insulin-dependent) diabetic patients to glutamate decarboxylase from rat tissues. Evidence for antigenic and non-antigenic forms of the enzyme. Diabetologia 35: 380, 1992.

    CAS  Google Scholar 

  109. Groop L., Miettinen A., Groop P.H., Meri S., Koskimies S., Bottazzo G.F. Organ-specific autoimmunity and HLA-DR antigens as markers for beta-cell destruction in patients with type II diabetes. Diabetes 37: 99, 1988.

    PubMed  CAS  Google Scholar 

  110. Di Mario U., Irvine W.J., Borsey D.Q., Kyner J.L., Weston J., Galfo C. Immune abnormalities in diabetic patients not requiring insulin at diagnosis. Diabetologia 25: 392, 1983.

    PubMed  Google Scholar 

  111. Tuomi T., Groop L.C., Zimmet P.Z., Rowley M.J., Knowles W., Mackay I.R. Antibodies to glutamic acid decarboxylase reveal latent autoimmune diabetes mellitus in adults with a non-insulin-dependent onset of disease. Diabetes 42: 359, 1993.

    PubMed  CAS  Google Scholar 

  112. Atkinson M.A., Kaufman D.L., Campbell L., Gibbs K.A., Shah S.C., Bu D.F., Erlander M.G., Tobin A.J., Maclaren N.K. Response of peripheral-blood mononuclear cells to glutamate decarboxylase in insulin-dependent diabetes. Lancet 339: 458, 1992.

    PubMed  CAS  Google Scholar 

  113. Harrison L.C., Honeyman M.C., DeAizpurua H.J., Schmidli R.S., Colman P.G., Tait B.D., Cram D.S. Inverse relation between humoral and cellular immunity to glutamic acid decarboxylase in subjects at risk of insulin-dependent diabetes. Lancet 341: 1365, 1993.

    PubMed  CAS  Google Scholar 

  114. Mitsumoto H., Schwartzman M.J., Estes M.L., Chou S.M., La Franchise E.F., De Camilli P., Solimena M. Sudden death and paroxysmal autonomie dysfunction in Stiff-man syndrome. J. Neurol. 238: 91, 1991.

    PubMed  CAS  Google Scholar 

  115. Pujol-Borrell R., Todd I., Doshi M., Gray D., Feldmann M., Bottazzo G.F. Differential expression and regulation of MHC products in the endocrine and exocrine cells of the human pancreas. Clin. Exp. Immunol. 65: 128.

  116. Wong G.H., Bartlett P.F., Clark-Lewis I., Battye F., Schrader J.W. Inducible expression of H-2 and la antigens on brain cells. Nature 310: 688, 1984.

    PubMed  CAS  Google Scholar 

  117. Joly E., Oldstone M.B. Neuronal cells are deficient in loading peptides onto MHC class I molecules. Neuron 8: 1185, 1992.

    PubMed  CAS  Google Scholar 

  118. Fohlman J., Friman G. Is juvenile diabetes a viral disease? Annals of Medicine 25: 569, 1993.

    PubMed  CAS  Google Scholar 

  119. Solimena M., De Camilli P. Diabetes: spotlight on a neuronal enzyme. Nature. 366: 15, 1993.

    PubMed  CAS  Google Scholar 

  120. Greif K.F., Erlander M.G., Tillakaratne N.J.K., Tobin A.J. Postnatal expression of glutamate decarboxylases in developing rat cerebellum. Neurochem. Res. 16: 235, 1991.

    PubMed  CAS  Google Scholar 

  121. Mamula M.J., Lin R.H., Janeway Jr C.A., Hardin J.A. Breaking T cell tolerance with foreign and self coimmunogens. A study of autoimmune B and T cell epitopes of cytochrome c. Journal of Immunology 149: 789, 1992.

    CAS  Google Scholar 

  122. Hafler D.A., Matsui M., Wucherpfennig K.W., Ota K., Weiner H.L. The potential of restricted T cell recognition of myelin basic protein epitopes in the therapy of multiple sclerosis Ann. N. Y. Acad. Sci. 636: 251, 1991.

    CAS  Google Scholar 

  123. Critchfield J.M., Racke M.K., Zuniga-Pflucker J.C., Cannella B., Raine C.S., Goverman J., Lenardo M.J. T cell deletion in high antigen dose therapy of autoimmune encephalomyelitis. Science 25: 1139, 1994.

    Google Scholar 

  124. Weiner H.L., Mackin G.A., Matsui M., Orav E.J., Khoury S.J., Dawson D.M., Hafler D.A. Double blind pilot trial of oral tolerization with myelin antigens in multiple sclerosis. Science 259: 1321, 1993.

    PubMed  CAS  Google Scholar 

  125. Tisch R., McDevitt H.O. Antigen-specific immunotherapy: is it a real possibility to combat T-cell-mediated autoimmunity? Proc. Nat. Acad. Sci. USA 91: 437, 1994.

    CAS  Google Scholar 

  126. Gelber C., Paborsky L., Singer S., McAteer D., Tisch R., Jolicoeur C., Buelow R., McDevitt H.O., Fathman C.G. Isolation of nonobese diabetic mice T-cells that recognize novel autoantigens involved in the early events of diabetes. Diabetes 43: 33, 1994.

    PubMed  CAS  Google Scholar 

  127. Craft J., Mamula M., Ohosone Y., Boire G., Gold H., Hardin J. snRNPs and scRNPs as autoantigens: clues to the etiology of the connective tissue diseases. Clin. Rheumat. 9: 10, 1990.

    CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Solimena, M., Butler, M.H. & De Camilli, P. GAD, diabetes, and Stiff-Man syndrome: Some progress and more questions. J Endocrinol Invest 17, 509–520 (1994). https://doi.org/10.1007/BF03347745

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF03347745

Keywords

Navigation