, Volume 35, Issue 6, pp 550–554 | Cite as

Antibodies to the Mr 64,000 (64K) protein in islet cell antibody positive non-diabetic individuals indicate high risk for impaired Beta-cell function

  • J. Seißler
  • B. Hering
  • W. Richter
  • M. Glück
  • N. Yassin
  • R. G. Bretzel
  • B. O. Boehm
  • K. Federlin
  • W. A. Scherbaum


A prospective study of a normal childhood population identified 44 islet cell antibody positive individuals. These subjects were typed for HLA DR and DQ alleles and investigated for the presence of antibodies to the Mr 64,000 (64K) islet cell antigen, complement-fixing islet cell antibodies and radiobinding insulin autoantibodies to determine their potency in detecting subjects with impaired Beta-cell function. At initial testing 64K antibodies were found in six of 44 islet cell antibody positive subjects (13.6%). The same sera were also positive for complement-fixing islet cell antibodies and five of them had insulin autoantibodies. During the follow-up at 18 months, islet cell antibodies remained detectable in 50% of the subjects studied. In all six cases who were originally positive, 64K antibodies were persistently detectable, whereas complement-fixing islet cell antibodies became negative in two of six and insulin autoantibodies in one of five individuals. HLA DR4 (p < 0.005) and absence of asparic acid (Asp) at position 57 of the HLA DQ β chain (p < 0.05) were significantly increased in subjects with 64K antibodies compared with control subjects. Of 40 individuals tested in the intravenous glucose tolerance test, three had a first phase insulin response below the first percentile of normal control subjects. Two children developed Type 1 (insulin-dependent) diabetes mellitus after 18 and 26 months, respectively. Each of these subjects was non-Asp homozygous and had persistent islet cell and 64K antibodies. We conclude that 64K antibodies, complement-fixing islet cell antibodies and insulin autoantibodies represent sensitive serological markers in assessing high risk for a progression to Type 1 diabetes in islet cell antibody positive non-diabetic individuals.

Key words

Population study 64K antibodies islet cell antibodies complement-fixing islet cell antibodies insulin autoantibodies HLA 


  1. 1.
    Trucco M, Dorman JS (1989) Immunogenetics of insulin-dependent diabetes mellitus in humans. CRC Critical Rev Immunol 9: 201–241Google Scholar
  2. 2.
    Todd JA, Bell JI, McDevitt HO (1987) HLA DQ β gene contributes to susceptibility and resistance to insulin-dependent diabetes mellitus. Nature 329: 599–604CrossRefPubMedGoogle Scholar
  3. 3.
    Srikanta S, Ganda OP, Rabizadeh A, Soeldner JS, Eisenbarth GS (1985) First degree relatives of patients with type I diabetes. Islet-cell antibodies and abnormal insulin secretion. N Engl J Med 313: 461–464PubMedGoogle Scholar
  4. 4.
    Tarn AC, Thomas JM, Dean BM et al. (1988) Predicting insulin-dependent diabetes. Lancet 1: 845–850PubMedGoogle Scholar
  5. 5.
    Riley WJ, MacLaren NK, Kirscher J et al. (1990) A prospective study of the development of diabetes in relatives of patients with insulin-dependent diabetes. N Engl J Med 323: 1167–1172Google Scholar
  6. 6.
    Johnston C, Millward BA, Hoskins P, Leslie RDG, Bottazzo GF, Pyke DA (1989) Islet-cell antibodies as predictors of the later development of Type 1 (insulin-dependent) diabetes. A study in identical twins. Diabetologia 32: 382–386PubMedGoogle Scholar
  7. 7.
    Ziegler AG, Ziegler R, Vardi P, Jackson RA, Soeldner JS, Eisenbarth GS (1989) Life-table analysis of progression to diabetes of anti-insulin autoantibody-positive relatives of individuals with type I diabetes. Diabetes 38: 1320–1325PubMedGoogle Scholar
  8. 8.
    Baekkeskov S, Aanstoot AJ, Christgau S et al. (1990) Identification of the 64K autoantigen in insulin-dependent diabetes as the GABA-synthesizing enzyme glutamic acid decarboxylase. Nature 347: 151–156CrossRefPubMedGoogle Scholar
  9. 9.
    Baekkeskov S (1986) Immunoreactivity to a 64,000 Mr human islet cell antigen in sera from insulin-dependent diabetes mellitus and individuals with abnormal glucose tolerance. Mol Biol Med 3: 137–142PubMedGoogle Scholar
  10. 10.
    Atkinson MA, MacLaren NK, Scharp DW, Lacy PE, Riley J (1990) 64.000 Mr autoantibodies as predictor of insulin-dependent diabetes. Lancet 1: 1357–1360CrossRefGoogle Scholar
  11. 11.
    Bärmeier H, McCulloch DK, Neifing JL, Warnock G, Rajotte RV, Palmer JP, Lernmark Å (1991) Risk for developing Type 1 (insulin-dependent) diabetes mellitus and the presence of islet 64K antibodies. Diabetologia 34: 727–733PubMedGoogle Scholar
  12. 12.
    Boehm BO, Manfras B, Seißler J et al. (1991) Epidemiology and immunogenetic background of islet cell antibody-positive nondiabetic schoolchildren. Ulm-Frankfurt population study. Diabetes 40: 1435–1439PubMedGoogle Scholar
  13. 13.
    Scherbaum WA, Hampl W, Muir P et al. (1991) No association between islet cell antibodies and coxsackie B, mumps, rubella and cytomegalovirus antibodies in non-diabetic individuals aged 7–19 years. Diabetologia 34: 835–838PubMedGoogle Scholar
  14. 14.
    Scherbaum WA, Mirakian AR, Pujol-Borrell R, Dean M, Bottazzo GF (1986) Immunochemistry in the study and diagnosis of organ-specific autoimmune diseases. In: Polak JM, Van Noorden S (eds) Immunochemistry. Modern methods and applications. Wright, Bistrol, pp 456–476Google Scholar
  15. 15.
    Christie MR, Pipeleers DG, Lernmark Å, Baekkeskov S (1990) Cellular and subcellular localization of an Mr 64,000 protein autoantigen in insulin-dependent diabetes. J Biol Chem 265: 376–381PubMedGoogle Scholar
  16. 16.
    Ricordi C, Lacy PE, Finke EH, Olack BJ, Scharp DW (1988) Automated method for isolation of human pancreatic islets. Diabetes 37: 413–420PubMedGoogle Scholar
  17. 17.
    Laemmli UK (1970) Cleavage and structural proteins during the assembly of the head of bacteriophage T4. Nature 227: 680–685PubMedGoogle Scholar
  18. 18.
    Vardi P, Sib SA, Tuttleman M et al. (1987) Competitive insulin autoantibody assay. Prospective evaluation of subjects at high risk for the development of type 1 diabetes mellitus. Diabetes 36: 1286–1291PubMedGoogle Scholar
  19. 19.
    Bergua M, Solé J, Marion G et al. (1987) Prevalence of islet cell antibodies, insulin antibodies and hyperglycaemia in 2291 schoolchildren. Diabetologia 30: 724–726PubMedGoogle Scholar
  20. 20.
    Bruining GJ, Molenaar JL, Grobbe DE et al. (1989) Ten-year follow-up study of islet-cell antibodies and childhood diabetes mellitus. Lancet 1: 1100–1103CrossRefPubMedGoogle Scholar
  21. 21.
    Karjalainen JK (1990) Islet cell antibodies as predictive markers for IDDM in children with high background incidence of disease. Diabetes 39: 1144–1150PubMedGoogle Scholar
  22. 22.
    Landin-Olsson M, Karlsson A, Dahlquist G, Blom L, Lernmark Å, Sundkvist G (1989) Islet cell and other organ-specific autoantibodies in all children developing Type 1 (insulin-dependent) diabetes mellitus in Sweden during one year and in matched control children. Diabetologia 32: 387–395CrossRefPubMedGoogle Scholar
  23. 23.
    Spencer KM, Tarn A, Dean BM, Lister J, Bottazzo GF (1984) Fluctuating islet-cell autoimmunity in unaffected relatives of patients with insulin-dependent diabetes. Lancet 1: 764–766CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 1992

Authors and Affiliations

  • J. Seißler
    • 1
  • B. Hering
    • 2
  • W. Richter
    • 1
  • M. Glück
    • 1
  • N. Yassin
    • 1
  • R. G. Bretzel
    • 2
  • B. O. Boehm
    • 3
  • K. Federlin
    • 2
  • W. A. Scherbaum
    • 1
  1. 1.Department of Internal Medicine IUniversity of UlmFRG
  2. 2.Third Department of MedicineUniversity of GießenFRG
  3. 3.Department of General MedicineUniversity of FrankfurtFRG

Personalised recommendations