Skip to main content
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1995 Apr;95(4):1505–1511. doi: 10.1172/JCI117822

Glutamate decarboxylase-, insulin-, and islet cell-antibodies and HLA typing to detect diabetes in a general population-based study of Swedish children.

W A Hagopian 1, C B Sanjeevi 1, I Kockum 1, M Landin-Olsson 1, A E Karlsen 1, G Sundkvist 1, G Dahlquist 1, J Palmer 1, A Lernmark 1
PMCID: PMC295633  PMID: 7706455

Abstract

Most autoimmune diabetes occurs in those without a diabetic relative, but few cases are identifiable prospectively. To model general population prediction, 491 consecutive newly diabetic children from all of Sweden were tested for autoantibodies to glutamate decarboxylase (GAD65ab), insulin (IAA), and islet cells (ICA), and for HLA-DQ genotypes by PCR; 415 matched control children were tested in parallel. GAD65ab sensitivity/specificity was 70/96%, versus 84/96% for ICA, 56/97% for IAA, 93/93% (any positive), 39/99.7% (all positive), and 41/99.7% (GAD65ab plus IAA). The latter's 25% predictive value was not improved by requiring concomitant high-risk HLA genotypes. GAD65ab were associated with DQA1*0501/B1*0201 (DQ2; P = 0.007) but not DQA1*0301/B1*0302 (DQ8), and IAA with DQA1*0301/B1*0302 (DQ8; P = 0.03) but not DQA1*0501/B1*0201 (DQ2). GAD65ab were more prevalent in females than males (79 vs. 63%; P < 0.0001) but did not vary with onset age nor season. Combining the three antibody assays yielded sufficient sensitivity for screening. GADab were relatively sensitive/specific for diabetes, but even with HLA marker combinations yielded predictive values insufficient for early immunointervention in the low-prevalence general population.

Full text

PDF
1505

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Baekkeskov S., Dyrberg T., Lernmark A. Autoantibodies to a 64-kilodalton islet cell protein precede the onset of spontaneous diabetes in the BB rat. Science. 1984 Jun 22;224(4655):1348–1350. doi: 10.1126/science.6374896. [DOI] [PubMed] [Google Scholar]
  2. Baekkeskov S., Landin M., Kristensen J. K., Srikanta S., Bruining G. J., Mandrup-Poulsen T., de Beaufort C., Soeldner J. S., Eisenbarth G., Lindgren F. Antibodies to a 64,000 Mr human islet cell antigen precede the clinical onset of insulin-dependent diabetes. J Clin Invest. 1987 Mar;79(3):926–934. doi: 10.1172/JCI112903. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Bloom A., Hayes T. M., Gamble D. R. Register of newly diagnosed diabetic children. Br Med J. 1975 Sep 6;3(5983):580–583. doi: 10.1136/bmj.3.5983.580. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Bottazzo G. F., Florin-Christensen A., Doniach D. Islet-cell antibodies in diabetes mellitus with autoimmune polyendocrine deficiencies. Lancet. 1974 Nov 30;2(7892):1279–1283. doi: 10.1016/s0140-6736(74)90140-8. [DOI] [PubMed] [Google Scholar]
  5. Buschard K., Brogren C. H., Röpke C., Rygaard J. Antigen expression of the pancreatic beta-cells is dependent on their functional state, as shown by a specific, BB rat monoclonal autoantibody IC2. APMIS. 1988 Apr;96(4):342–346. doi: 10.1111/j.1699-0463.1988.tb05313.x. [DOI] [PubMed] [Google Scholar]
  6. Castaño L., Russo E., Zhou L., Lipes M. A., Eisenbarth G. S. Identification and cloning of a granule autoantigen (carboxypeptidase-H) associated with type I diabetes. J Clin Endocrinol Metab. 1991 Dec;73(6):1197–1201. doi: 10.1210/jcem-73-6-1197. [DOI] [PubMed] [Google Scholar]
  7. Dahlquist G., Blom L., Lönnberg G. The Swedish Childhood Diabetes Study--a multivariate analysis of risk determinants for diabetes in different age groups. Diabetologia. 1991 Oct;34(10):757–762. doi: 10.1007/BF00401524. [DOI] [PubMed] [Google Scholar]
  8. Dahlquist G., Blom L., Tuvemo T., Nyström L., Sandström A., Wall S. The Swedish childhood diabetes study--results from a nine year case register and a one year case-referent study indicating that type 1 (insulin-dependent) diabetes mellitus is associated with both type 2 (non-insulin-dependent) diabetes mellitus and autoimmune disorders. Diabetologia. 1989 Jan;32(1):2–6. doi: 10.1007/BF00265396. [DOI] [PubMed] [Google Scholar]
  9. Eisenbarth G. S., Jackson R. A., Pugliese A. Insulin autoimmunity: the rate limiting factor in pre-type I diabetes. J Autoimmun. 1992 Apr;5 (Suppl A):241–246. doi: 10.1016/0896-8411(92)90039-s. [DOI] [PubMed] [Google Scholar]
  10. Greenbaum C. J., Palmer J. P., Nagataki S., Yamaguchi Y., Molenaar J. L., Van Beers W. A., MacLaren N. K., Lernmark A. Improved specificity of ICA assays in the Fourth International Immunology of Diabetes Serum Exchange Workshop. Diabetes. 1992 Dec;41(12):1570–1574. doi: 10.2337/diab.41.12.1570. [DOI] [PubMed] [Google Scholar]
  11. Hagopian W. A., Karlsen A. E., Gottsäter A., Landin-Olsson M., Grubin C. E., Sundkvist G., Petersen J. S., Boel E., Dyrberg T., Lernmark A. Quantitative assay using recombinant human islet glutamic acid decarboxylase (GAD65) shows that 64K autoantibody positivity at onset predicts diabetes type. J Clin Invest. 1993 Jan;91(1):368–374. doi: 10.1172/JCI116195. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Hagopian W. A., Karlsen A. E., Petersen J. S., Teague J., Gervassi A., Jiang J., Fujimoto W., Lernmark A. Regulation of glutamic acid decarboxylase diabetes autoantigen expression in highly purified isolated islets from Macaca nemestrina. Endocrinology. 1993 Jun;132(6):2674–2681. doi: 10.1210/endo.132.6.8504767. [DOI] [PubMed] [Google Scholar]
  13. 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. 1993 May 29;341(8857):1365–1369. doi: 10.1016/0140-6736(93)90940-i. [DOI] [PubMed] [Google Scholar]
  14. Kockum I., Wassmuth R., Holmberg E., Michelsen B., Lernmark A. HLA-DQ primarily confers protection and HLA-DR susceptibility in type I (insulin-dependent) diabetes studied in population-based affected families and controls. Am J Hum Genet. 1993 Jul;53(1):150–167. [PMC free article] [PubMed] [Google Scholar]
  15. Landin-Olsson M., Palmer J. P., Lernmark A., Blom L., Sundkvist G., Nyström L., Dahlquist G. Predictive value of islet cell and insulin autoantibodies for type 1 (insulin-dependent) diabetes mellitus in a population-based study of newly-diagnosed diabetic and matched control children. Diabetologia. 1992 Nov;35(11):1068–1073. doi: 10.1007/BF02221683. [DOI] [PubMed] [Google Scholar]
  16. Landin-Olsson M. Precision of the islet-cell antibody assay depends on the pancreas. J Clin Lab Anal. 1990;4(4):289–294. doi: 10.1002/jcla.1860040410. [DOI] [PubMed] [Google Scholar]
  17. Madsen O. D., Olsson M. L., Bille G., Sundkvist G., Lernmark A., Dahlqvist G., Ludvigsson J. A two-colour immunofluorescence test with a monoclonal human proinsulin antibody improves the assay for islet cell antibodies. Diabetologia. 1986 Feb;29(2):115–118. doi: 10.1007/BF00456121. [DOI] [PubMed] [Google Scholar]
  18. Nyström L., Dahlquist G., Rewers M., Wall S. The Swedish childhood diabetes study. An analysis of the temporal variation in diabetes incidence 1978-1987. Int J Epidemiol. 1990 Mar;19(1):141–146. doi: 10.1093/ije/19.1.141. [DOI] [PubMed] [Google Scholar]
  19. Palmer J. P. Insulin autoantibodies: their role in the pathogenesis of IDDM. Diabetes Metab Rev. 1987 Oct;3(4):1005–1015. doi: 10.1002/dmr.5610030409. [DOI] [PubMed] [Google Scholar]
  20. Petersen J. S., Hejnaes K. R., Moody A., Karlsen A. E., Marshall M. O., Høier-Madsen M., Boel E., Michelsen B. K., Dyrberg T. Detection of GAD65 antibodies in diabetes and other autoimmune diseases using a simple radioligand assay. Diabetes. 1994 Mar;43(3):459–467. doi: 10.2337/diab.43.3.459. [DOI] [PubMed] [Google Scholar]
  21. Pietropaolo M., Castaño L., Babu S., Buelow R., Kuo Y. L., Martin S., Martin A., Powers A. C., Prochazka M., Naggert J. Islet cell autoantigen 69 kD (ICA69). Molecular cloning and characterization of a novel diabetes-associated autoantigen. J Clin Invest. 1993 Jul;92(1):359–371. doi: 10.1172/JCI116574. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Richter W., Shi Y., Baekkeskov S. Autoreactive epitopes defined by diabetes-associated human monoclonal antibodies are localized in the middle and C-terminal domains of the smaller form of glutamate decarboxylase. Proc Natl Acad Sci U S A. 1993 Apr 1;90(7):2832–2836. doi: 10.1073/pnas.90.7.2832. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Riley W. J., Maclaren N. K., Krischer J., Spillar R. P., Silverstein J. H., Schatz D. A., Schwartz S., Malone J., Shah S., Vadheim C. A prospective study of the development of diabetes in relatives of patients with insulin-dependent diabetes. N Engl J Med. 1990 Oct 25;323(17):1167–1172. doi: 10.1056/NEJM199010253231704. [DOI] [PubMed] [Google Scholar]
  24. Robert J. J., Deschamps I., Chevenne D., Roger M., Mogenet A., Boitard C. Relationship between first-phase insulin secretion and age, HLA, islet cell antibody status, and development of type I diabetes in 220 juvenile first-degree relatives of diabetic patients. Diabetes Care. 1991 Aug;14(8):718–723. doi: 10.2337/diacare.14.8.718. [DOI] [PubMed] [Google Scholar]
  25. Roll U., Christie M. R., Standl E., Ziegler A. G. Associations of anti-GAD antibodies with islet cell antibodies and insulin autoantibodies in first-degree relatives of type I diabetic patients. Diabetes. 1994 Jan;43(1):154–160. doi: 10.2337/diab.43.1.154. [DOI] [PubMed] [Google Scholar]
  26. Rowe R. E., Leech N. J., Nepom G. T., McCulloch D. K. High genetic risk for IDDM in the Pacific Northwest. First report from the Washington State Diabetes Prediction Study. Diabetes. 1994 Jan;43(1):87–94. doi: 10.2337/diab.43.1.87. [DOI] [PubMed] [Google Scholar]
  27. Sanjeevi C. B., Zeidler A., Shaw S., Rotter J., Nepom G. T., Costin G., Raffel L., Eastman S., Kockum I., Wassmuth R. Analysis of HLA-DQA1 and -DQB1 genes in Mexican Americans with insulin-dependent diabetes mellitus. Tissue Antigens. 1993 Aug;42(2):72–77. doi: 10.1111/j.1399-0039.1993.tb02240.x. [DOI] [PubMed] [Google Scholar]
  28. Schmidli R. S., Colman P. G., Bonifacio E., Bottazzo G. F., Harrison L. C. High level of concordance between assays for glutamic acid decarboxylase antibodies. The First International Glutamic Acid Decarboxylase Antibody Workshop. Diabetes. 1994 Aug;43(8):1005–1009. doi: 10.2337/diab.43.8.1005. [DOI] [PubMed] [Google Scholar]
  29. Serjeantson S. W., Court J., Mackay I. R., Matheson B., Rowley M. J., Tuomi T., Wilson J. D., Zimmet P. HLA-DQ genotypes are associated with autoimmunity to glutamic acid decarboxylase in insulin-dependent diabetes mellitus patients. Hum Immunol. 1993 Oct;38(2):97–104. doi: 10.1016/0198-8859(93)90525-6. [DOI] [PubMed] [Google Scholar]
  30. Teruya M., Takei S., Forrest L. E., Grunewald A., Chan E. K., Charles M. A. Pancreatic islet function in nondiabetic and diabetic BB rats. Diabetes. 1993 Sep;42(9):1310–1317. doi: 10.2337/diab.42.9.1310. [DOI] [PubMed] [Google Scholar]
  31. Thivolet C. H., Tappaz M., Durand A., Petersen J., Stefanutti A., Chatelain P., Vialettes B., Scherbaum W., Orgiazzi J. Glutamic acid decarboxylase (GAD) autoantibodies are additional predictive markers of type 1 (insulin-dependent) diabetes mellitus in high risk individuals. Diabetologia. 1992 Jun;35(6):570–576. doi: 10.1007/BF00400486. [DOI] [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES