, Volume 36, Issue 11, pp 1155–1162 | Cite as

Insulin autoantibodies and high titre islet cell antibodies are preferentially associated with the HLA DQA1*0301-DQB1*0302 haplotype at clinical onset of Type 1 (insulin-dependent) diabetes mellitus before age 10 years, but not at onset between age 10 and 40 years

  • C. L. Vandewalle
  • T. Decraene
  • F. C. Schuit
  • I. H. De Leeuw
  • D. G. PipeIeers
  • F. K. Gorus
  • The Belgian Diabetes Registry


Demographic and biological data were collected from all Caucasian Type 1 diabetic patients (n = 279) who were recruited at clinical onset by the Belgian Diabetes Registry over 34 months. The male/female ratio was significantly higher for onset between age 20 and 40 years (2.4) than before age 20 years (1.0); no age-or sex-differences were noticed in serum fructosamine concentration. Total and high concentrations of insulin autoantibodies and islet cell antibodies were preferentially associated with the HLA DQA1*0301-DQB1*0302 susceptibility haplotype. The occurrence of both types of antibodies was also correlated, irrespective of haplotype. At onset before age 10 years, the high risk genotype DQA1*0301-DQB1*0302/DQA1*0501-DQB1*0201 was more prevalent than all other DQA1-DQB1 genotypes taken together, leading to a higher prevalence of the DQA1*0301-DQB1*0302 haplotype in this age group (75%) than in the 10–39 years age group (54%). Under age 10 years, the presence of DQA1*0301-DQB1*0302 was strongly associated with insulin autoantibodies (90%) and islet cell autoantibodies (92% with 85% of high titre), whereas patients without this haplotype were less frequently positive for insulin autoantibodies (31%) or islet cell autoantibodies (38% high titre). In the group with onset at age 10–39 years, the DQA1*0301-DQB1*0302 haplotype presented a lower association with insulin autoantibodies (∼40%) and islet cell autoantibodies (50 to 65% high titre), prevalences which no longer differed from those in subjects lacking this haplotype. The present data demonstrate that variations in prevalence of insulin autoantibodies and islet cell autoantibodies at onset of Type 1 diabetes can result from differences in age and in the fraction of patients with the HLA DQA1*0301-DQB1*0302 haplotype. The presence of this susceptibility haplotype at onset under age 10 years identifies a sub-group of patients with more than 90% positivity for insulin autoantibodies and more than 90% positivity for islet cell autoantibodies. It is conceivable that this sub-group can be recognized in the pre-diabetic phase through screening for immunological and genetic markers.

Key words

Diabetes mellitus insulin autoantibodies islet cell antibodies HLA DQ genotyping diabetes registries 


  1. 1.
    Baekkeskov S, Aanstoot HJ, Christgau S et al. (1990) Identification of the 64k autoantigen in insulin-dependent diabetes as the GABA-synthesizing enzyme glutamic acid decarboxylase. Nature (Lond) 347: 151–156Google Scholar
  2. 2.
    Christie MR, Tun RYM, Lo SSS et al. (1992) Antibodies to GAD and tryptic fragments of islet 64K antigens as distinct markers for development of type 1 diabetes: studies with identical twins. Diabetes 41: 782–787PubMedGoogle Scholar
  3. 3.
    Karjalainen J, Martin JM, Knip M et al. (1992) A bovine albumin peptide as a possible trigger of insulin-dependent diabetes mellitus. N Engl J Med 327: 302–307PubMedGoogle Scholar
  4. 4.
    Tarn A, Thomas J, Dean B et al. (1988) Predicting insulin-dependent diabetes. Lancet I: 845–850CrossRefGoogle Scholar
  5. 5.
    Maclaren NK (1988) How, when and why to predict type 1 diabetes. Diabetes 37: 1591–1594PubMedGoogle Scholar
  6. 6.
    Bruining GJ, Molenaar JL, Grobbee DE et al. (1989) Ten-year follow-up study of islet cell antibodies and childhood diabetes mellitus. Lancet I: 1100–1103CrossRefGoogle 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 1 diabetes. Diabetes 38: 1320–1325PubMedGoogle Scholar
  8. 8.
    Bonifacio E, Bingley PJ, Shattock H et al. (1990) Quantification of islet-cell antibodies and prediction of insulin-dependent diabetes. Lancet 335: 147–149CrossRefPubMedGoogle Scholar
  9. 9.
    Karjalainen JK (1990) Islet cell antibodies as predictive markers for type 1 diabetes in children with high background incidence of the disease. Diabetes 39: 1144–1150PubMedGoogle Scholar
  10. 10.
    Palmer JP, McCulloch DK (1991) Prediction and prevention of type 1 diabetes. Diabetes 40: 943–947PubMedGoogle Scholar
  11. 11.
    Nepom GT (1990) A unified hypothesis for the complex genetics of HLA associations with type 1 diabetes. Diabetes 39: 1153–1157PubMedGoogle Scholar
  12. 12.
    Baisch JM, Weeks T, Giles R, Hoover M, Stastry P, Capra JD (1990) Analysis of HLA-DQ genotypes and susceptibility in insulin-dependent diabetes mellitus. N Engl J Med 322: 1836–1841PubMedGoogle Scholar
  13. 13.
    Altaian DM, Sansom D, Marsh SGE (1991) What is the basis for HLA-DQ association with autoimmune disease? Immunol Today 12: 267–270CrossRefPubMedGoogle Scholar
  14. 14.
    Deschamps I, Beressi JP, Khalil I, Robert J (1991) The role of genetic predisposition to type 1 (insulin-dependent) diabetes mellitus. Ann Med 23: 427–435PubMedGoogle Scholar
  15. 15.
    Sheeny MJ (1992) HLA and insulin-dependent diabetes: a protective perspective. Diabetes 41: 123–129PubMedGoogle Scholar
  16. 16.
    Heimberg H, Nagy ZP, Somers G, De Leeuw I, Schuit F (1992) Complementation of HLA DQA and DQB genes confers susceptibility and protection to insulin-dependent diabetes mellitus. Hum Immunol 33: 10–17PubMedGoogle Scholar
  17. 17.
    Ziegler AG, Standl E, Albert E, Mehnert H (1991) HLA-associated insulin autoantibody formation in newly diagnosed type 1 diabetic patients. Diabetes 40: 1146–1149PubMedGoogle Scholar
  18. 18.
    Boehm BO, Manfras B, Seissler S et al. (1991) Epidemiology and immunogenetic background of islet cell antibody-positive nondiabetic schoolchildren. Ulm-Frankfurt population study. Diabetes 40: 1435–1439PubMedGoogle Scholar
  19. 19.
    Deschamps I, Boitard C, Hors J et al. (1992) Life table analysis of the risk of type 1 (insulin-dependent) diabetes mellitus in siblings according to islet cell antibodies and HLA markers. An 8-year prospective study. Diabetologia 35: 951–957PubMedGoogle Scholar
  20. 20.
    Gorus FK, Vandewalle CL, Schuit FC, Pipeleers DG and The Belgian Diabetes Registry (1992) Associations between genetic risk markers and autoantibodies in first degree relatives of patients with type 1 diabetes. Diabetologia 35: 208 (Abstract)PubMedGoogle Scholar
  21. 21.
    Eisenbarth GS (1986) Type 1 diabetes mellitus: a chronic autoimmune disease. N Engl J Med 314: 1360–1368PubMedGoogle Scholar
  22. 22.
    Decraene T, Vandewalle CL, Pipeleers DG, Gorus FK and the Belgian Diabetes Registry (1992) Increased concentrations of total IgM at onset of type 1 (insulin-dependent) diabetes: correlation with IgM binding to cells. Clin Chem 38: 1762–1767PubMedGoogle Scholar
  23. 23.
    National Diabetes Data Group (1979) Classification and diagnosis of diabetes mellitus and other categories of glucose intolerance. Diabetes 28: 1039–1057PubMedGoogle Scholar
  24. 24.
    Bodmer JG, Marsh SGE, Parham P et al. (1990) Nomenclature for factors of the HLA system, 1989. Tissue Antigens 35: 1–8PubMedGoogle Scholar
  25. 25.
    Gorus FK, Sodoyez J-C, Pipeleers DG et al. (1992) Detection of autoantibodies against islet amyloid polypeptide in human serum. Lack of association with type 1 (insulin-dependent) diabetes mellitus, or conditions favouring amyloid deposition in islets. Diabetologia 35: 1080–1086PubMedGoogle Scholar
  26. 26.
    Palmer JP, Asplin CM, Clemons P et al. (1983) Insulin antibodies in insulin-dependent diabetics before insulin treatment. Science 222: 1337–1339PubMedGoogle Scholar
  27. 27.
    Srikanta S, Ricker AT, McCulloch DK, Soeldner JS, Eisenbarth GS, Palmer JP (1986) Autoimmunity to insulin, beta cell dysfunction, and development of insulin-dependent diabetes mellitus. Diabetes 35: 139–142PubMedGoogle Scholar
  28. 28.
    Bottazzo GF, Florin-Christensen A, Doniach D (1974) Islet cell antibodies in diabetes mellitus with autoimmune polyendocrine deficiencies. Lancet II: 1279–1283CrossRefGoogle Scholar
  29. 29.
    Baker J, Metcalf P, Scragg R, Johnson R (1991) Fructosamine Test-Plus modified fructosamine assay evaluated. Clin Chem 37: 552–556PubMedGoogle Scholar
  30. 30.
    De Schepper J, Derde MP, Goubert P, Gorus F (1988) Reference values for serum fructosamine concentrations in children: influence of protein concentration, age and sex. Clin Chem 34: 2444–2447PubMedGoogle Scholar
  31. 31.
    Reijonen H, Ilonen J, Knip M, Akerblom K (1991) HLA-DQB1 alleles and absence of Asp 57 as susceptibility factors of type 1 diabetes in Finland. Diabetes 40: 1640–1677PubMedGoogle Scholar
  32. 32.
    Karjalainen J, Salmela P, Ilonen J, Surcel HM, Knip M (1989) A comparison of childhood and adult type 1 diabetes mellitus. N Engl J Med 320: 881–886PubMedGoogle Scholar
  33. 33.
    Landin-Olsson M, Karlsson FA, Lernmark Å, Sundkvist G and the Diabetes Incidence Study in Sweden Group (1992) Islet cell and thyrogastric antibodies in 633 consecutive 15- to 34 year-old patients in the Diabetes Incidence Study in Sweden. Diabetes 41: 1022–1027PubMedGoogle Scholar
  34. 34.
    Wilkin TJ (1991) Autoantibodies as mechanisms, markers and mediators of B-cell disease. Diab Metab Rev 7: 105–120Google Scholar
  35. 35.
    Palmer JP (1987) Insulin autoantibodies: their role in the pathogenesis of type 1 diabetes. Diab Metab Rev 3: 1005–1015Google Scholar
  36. 36.
    Spinas GA, Matler L, Wilkin T, Staffelbach O, Berger W (1988) Islet-cell and insulin autoantibodies in first degree relatives of type 1 diabetes: a 5-year follow-up study in a Swiss population. Adv Exp Med Biol 246: 209–214PubMedGoogle Scholar
  37. 37.
    Arslanian SA, Becker DJ, Rabin B et al. (1986) Correlates of insulin antibodies in newly diagnosed children with insulin-dependent diabetes before insulin therapy. Diabetes 35: 634–641PubMedGoogle Scholar
  38. 38.
    Wilkin T, Armitage M, Casey C et al. (1985) Value of insulin autoantibodies as serum markers for insulin-dependent diabetes mellitus. Lancet I: 480–482CrossRefGoogle Scholar
  39. 39.
    Atkinson MA, Maclaren NK, Riley WJ, Winter WE, Fisk DD, Spillar RP (1986) Are insulin autoantibodies markers for insulin-dependent diabetes mellitus? Diabetes 35: 894–898PubMedGoogle Scholar
  40. 40.
    Ziegler R, Alper CA, Awdeh ZL et al. (1991) Specific association of HLA-DR4 with increased prevalence and concentrations of insulin autoantibodies in first-degree relatives of patients with type 1 diabetes. Diabetes 40: 709–714PubMedGoogle Scholar
  41. 41.
    Vexiau P, Helmy-Khalil S, Deschamps I et al. (1988) Organ-specific autoantibodies in HLA genotyped insulin-dependent diabetes mellitus families. J Autoimmun 1: 253–261CrossRefPubMedGoogle Scholar
  42. 42.
    Pagano G, Cavallo-Perin P, Cavalot F et al. (1987) Genetic, immunologic and environmental heterogeneity of type 1 diabetes: incidence and 12-mo follow-up of an Italian population. Diabetes 36: 859–863PubMedGoogle Scholar
  43. 43.
    Dean BM, Becker F, McNally JM et al. (1986) Insulin autoantibodies in the prediabetic period: correlation with islet cell antibodies and development of diabetes. Diabetologia 29: 339–342PubMedGoogle Scholar
  44. 44.
    Vardi P, Ziegler AG, Mathews JH et al. (1988) Concentrations of insulin antibodies at onset of type 1 diabetes: inverse log-linear correlation with age. Diabetes Care 11: 736–739PubMedGoogle Scholar
  45. 45.
    Caillat-Zucman S, Garchon H-Y, Timsit J et al. (1992) Age-dependent HLA genetic heterogeneity of type 1 (insulin-dependent) diabetes mellitus. J Clin Invest 90: 2241–2250Google Scholar
  46. 46.
    Krolewski AS, Warram JH, Rand LI, Kahn CR (1987) Epidemiologic approach to the etiology of type 1 diabetes mellitus and its complications. N Engl J Med 317: 1390–1398PubMedGoogle Scholar

Copyright information

© Springer-Verlag 1993

Authors and Affiliations

  • C. L. Vandewalle
    • 1
  • T. Decraene
    • 1
  • F. C. Schuit
    • 1
  • I. H. De Leeuw
    • 2
  • D. G. PipeIeers
    • 1
  • F. K. Gorus
    • 1
  • The Belgian Diabetes Registry
    • 3
  1. 1.Diabetes Research CentreVrije Universiteit BrusselBrusselsBelgium
  2. 2.Department of EndocrinologyUniversitaire Instelling AntwerpenAntwerpBelgium
  3. 3.BDRBrusselsBelgium

Personalised recommendations