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. 1998 Jan 15;101(2):327–336. doi: 10.1172/JCI119879

Prediction of insulin-dependent diabetes mellitus in siblings of children with diabetes. A population-based study. The Childhood Diabetes in Finland Study Group.

P Kulmala 1, K Savola 1, J S Petersen 1, P Vähäsalo 1, J Karjalainen 1, T Löppönen 1, T Dyrberg 1, H K Akerblom 1, M Knip 1
PMCID: PMC508571  PMID: 9435304

Abstract

An unselected population of 755 siblings of children with insulin-dependent diabetes mellitus (IDDM) was studied to evaluate the predictive characteristics of islet cell antibodies (ICA), antibodies to the IA-2 protein (IA-2A), antibodies to the 65-kD isoform of glutamic acid decarboxylase (GADA), insulin autoantibodies (IAA), and combinations of these markers. We also evaluated whether the histochemical ICA test could be replaced by the combined detection of other markers. 32 siblings progressed to IDDM within 7.7 yr of the initial sample taken at or close to the diagnosis of the index case (median follow-up, 9.1 yr). The positive predictive values of ICA, IA-2A, GADA, and IAA were 43, 55, 42, and 29%, and their sensitivities 81, 69, 69, and 25%, respectively. In contrast to the other three antibody specificities, GADA levels were not related to the risk for IDDM. The risk for IDDM in siblings with four, three, two, one, or no antibodies was 40, 70, 25, 2, and 0.8%, respectively. Combined screening for IA-2A and GADA identified 70% of all ICA-positive siblings, and all of the ICA-positive progressors were also positive for at least one of the three other markers. The sensitivity of the combined analysis of IA-2A and GADA was 81%, and the positive predictive value was 41%. In conclusion, combined screening for IA-2A and GADA may replace the ICA assay, giving comparable sensitivity, specificity, and positive predictive value. Accurate assessment of the risk for IDDM in siblings is complicated, as not even all those with four antibody specificities contract the disease, and some with only one or no antibodies initially will progress to IDDM.

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Selected References

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  1. Atkinson M. A., Maclaren N. K., Scharp D. W., Lacy P. E., Riley W. J. 64,000 Mr autoantibodies as predictors of insulin-dependent diabetes. Lancet. 1990 Jun 9;335(8702):1357–1360. doi: 10.1016/0140-6736(90)91241-2. [DOI] [PubMed] [Google Scholar]
  2. Atkinson M. A., Maclaren N. K. What causes diabetes? Sci Am. 1990 Jul;263(1):62-3, 66-71. doi: 10.1038/scientificamerican0790-62. [DOI] [PubMed] [Google Scholar]
  3. Baekkeskov S., Aanstoot H. J., Christgau S., Reetz A., Solimena M., Cascalho M., Folli F., Richter-Olesen H., De Camilli P., Camilli P. D. Identification of the 64K autoantigen in insulin-dependent diabetes as the GABA-synthesizing enzyme glutamic acid decarboxylase. Nature. 1990 Sep 13;347(6289):151–156. doi: 10.1038/347151a0. [DOI] [PubMed] [Google Scholar]
  4. 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]
  5. Baekkeskov S., Nielsen J. H., Marner B., Bilde T., Ludvigsson J., Lernmark A. Autoantibodies in newly diagnosed diabetic children immunoprecipitate human pancreatic islet cell proteins. Nature. 1982 Jul 8;298(5870):167–169. doi: 10.1038/298167a0. [DOI] [PubMed] [Google Scholar]
  6. Bingley P. J., Christie M. R., Bonifacio E., Bonfanti R., Shattock M., Fonte M. T., Bottazzo G. F., Gale E. A. Combined analysis of autoantibodies improves prediction of IDDM in islet cell antibody-positive relatives. Diabetes. 1994 Nov;43(11):1304–1310. doi: 10.2337/diab.43.11.1304. [DOI] [PubMed] [Google Scholar]
  7. Bonifacio E., Bingley P. J., Shattock M., Dean B. M., Dunger D., Gale E. A., Bottazzo G. F. Quantification of islet-cell antibodies and prediction of insulin-dependent diabetes. Lancet. 1990 Jan 20;335(8682):147–149. doi: 10.1016/0140-6736(90)90013-u. [DOI] [PubMed] [Google Scholar]
  8. Bonifacio E., Genovese S., Braghi S., Bazzigaluppi E., Lampasona V., Bingley P. J., Rogge L., Pastore M. R., Bognetti E., Bottazzo G. F. Islet autoantibody markers in IDDM: risk assessment strategies yielding high sensitivity. Diabetologia. 1995 Jul;38(7):816–822. doi: 10.1007/s001250050358. [DOI] [PubMed] [Google Scholar]
  9. Bonifacio E., Lampasona V., Genovese S., Ferrari M., Bosi E. Identification of protein tyrosine phosphatase-like IA2 (islet cell antigen 512) as the insulin-dependent diabetes-related 37/40K autoantigen and a target of islet-cell antibodies. J Immunol. 1995 Dec 1;155(11):5419–5426. [PubMed] [Google Scholar]
  10. 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]
  11. Bärmeier H., McCulloch D. K., Neifing J. L., Warnock G., Rajotte R. V., Palmer J. P., Lernmark A. Risk for developing type 1 (insulin-dependent) diabetes mellitus and the presence of islet 64K antibodies. Diabetologia. 1991 Oct;34(10):727–733. doi: 10.1007/BF00401518. [DOI] [PubMed] [Google Scholar]
  12. Castaño L., Eisenbarth G. S. Type-I diabetes: a chronic autoimmune disease of human, mouse, and rat. Annu Rev Immunol. 1990;8:647–679. doi: 10.1146/annurev.iy.08.040190.003243. [DOI] [PubMed] [Google Scholar]
  13. Christie M. R., Roll U., Payton M. A., Hatfield E. C., Ziegler A. G. Validity of screening for individuals at risk for type I diabetes by combined analysis of antibodies to recombinant proteins. Diabetes Care. 1997 Jun;20(6):965–970. doi: 10.2337/diacare.20.6.965. [DOI] [PubMed] [Google Scholar]
  14. Christie M., Landin-Olsson M., Sundkvist G., Dahlquist G., Lernmark A., Baekkeskov S. Antibodies to a Mr-64,000 islet cell protein in Swedish children with newly diagnosed type 1 (insulin-dependent) diabetes. Diabetologia. 1988 Aug;31(8):597–602. doi: 10.1007/BF00264766. [DOI] [PubMed] [Google Scholar]
  15. Cooke A. An overview on possible mechanisms of destruction of the insulin-producing beta cell. Curr Top Microbiol Immunol. 1990;164:125–142. doi: 10.1007/978-3-642-75741-9_7. [DOI] [PubMed] [Google Scholar]
  16. Dahlquist G., Blom L., Holmgren G., Hägglöf B., Larsson Y., Sterky G., Wall S. The epidemiology of diabetes in Swedish children 0-14 years--a six-year prospective study. Diabetologia. 1985 Nov;28(11):802–808. doi: 10.1007/BF00291068. [DOI] [PubMed] [Google Scholar]
  17. Deschamps I., Boitard C., Hors J., Busson M., Marcelli-Barge A., Mogenet A., Robert J. J. 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. 1992 Oct;35(10):951–957. doi: 10.1007/BF00401424. [DOI] [PubMed] [Google Scholar]
  18. Gepts W. Pathologic anatomy of the pancreas in juvenile diabetes mellitus. Diabetes. 1965 Oct;14(10):619–633. doi: 10.2337/diab.14.10.619. [DOI] [PubMed] [Google Scholar]
  19. Gorsuch A. N., Spencer K. M., Lister J., McNally J. M., Dean B. M., Bottazzo G. F., Cudworth A. G. Evidence for a long prediabetic period in type I (insulin-dependent) diabetes mellitus. Lancet. 1981 Dec 19;2(8260-61):1363–1365. doi: 10.1016/s0140-6736(81)92795-1. [DOI] [PubMed] [Google Scholar]
  20. Gorus F. K., Goubert P., Semakula C., Vandewalle C. L., De Schepper J., Scheen A., Christie M. R., Pipeleers D. G. IA-2-autoantibodies complement GAD65-autoantibodies in new-onset IDDM patients and help predict impending diabetes in their siblings. The Belgian Diabetes Registry. Diabetologia. 1997 Jan;40(1):95–99. doi: 10.1007/s001250050648. [DOI] [PubMed] [Google Scholar]
  21. 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]
  22. Karjalainen J. K. Islet cell antibodies as predictive markers for IDDM in children with high background incidence of disease. Diabetes. 1990 Sep;39(9):1144–1150. doi: 10.2337/diab.39.9.1144. [DOI] [PubMed] [Google Scholar]
  23. Krischer J. P., Schatz D., Riley W. J., Spillar R. P., Silverstein J. H., Schwartz S., Malone J., Shah S., Vadheim C. M., Rotter J. I. Insulin and islet cell autoantibodies as time-dependent covariates in the development of insulin-dependent diabetes: a prospective study in relatives. J Clin Endocrinol Metab. 1993 Sep;77(3):743–749. doi: 10.1210/jcem.77.3.8370696. [DOI] [PubMed] [Google Scholar]
  24. Lendrum R., Walker G., Gamble D. R. Islet-cell antibodies in juvenile diabetes mellitus of recent onset. Lancet. 1975 Apr 19;1(7912):880–882. doi: 10.1016/s0140-6736(75)91683-9. [DOI] [PubMed] [Google Scholar]
  25. Palmer J. P., Asplin C. M., Clemons P., Lyen K., Tatpati O., Raghu P. K., Paquette T. L. Insulin antibodies in insulin-dependent diabetics before insulin treatment. Science. 1983 Dec 23;222(4630):1337–1339. doi: 10.1126/science.6362005. [DOI] [PubMed] [Google Scholar]
  26. Passini N., Larigan J. D., Genovese S., Appella E., Sinigaglia F., Rogge L. The 37/40-kilodalton autoantigen in insulin-dependent diabetes mellitus is the putative tyrosine phosphatase IA-2. Proc Natl Acad Sci U S A. 1995 Sep 26;92(20):9412–9416. doi: 10.1073/pnas.92.20.9412. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Payton M. A., Hawkes C. J., Christie M. R. Relationship of the 37,000- and 40,000-M(r) tryptic fragments of islet antigens in insulin-dependent diabetes to the protein tyrosine phosphatase-like molecule IA-2 (ICA512). J Clin Invest. 1995 Sep;96(3):1506–1511. doi: 10.1172/JCI118188. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. 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]
  29. 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]
  30. 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]
  31. Sabbah E., Kulmala P., Veijola R., Vähäsalo P., Karjalainen J., Tuomilehto-Wolf E., Akerblom H. K., Knip M. Glutamic acid decarboxylase antibodies in relation to other autoantibodies and genetic risk markers in children with newly diagnosed insulin-dependent diabetes. Childhood Diabetes in Finland Study Group. J Clin Endocrinol Metab. 1996 Jul;81(7):2455–2459. doi: 10.1210/jcem.81.7.8675560. [DOI] [PubMed] [Google Scholar]
  32. Schmidli R. S., Colman P. G., Bonifacio E. Disease sensitivity and specificity of 52 assays for glutamic acid decarboxylase antibodies. The Second International GADAB Workshop. Diabetes. 1995 Jun;44(6):636–640. doi: 10.2337/diab.44.6.636. [DOI] [PubMed] [Google Scholar]
  33. Schmidli R. S., Colman P. G., Harrison L. C. Do glutamic acid decarboxylase antibodies improve the prediction of IDDM in first-degree relatives at risk for IDDM? J Autoimmun. 1994 Dec;7(6):873–879. doi: 10.1006/jaut.1994.1071. [DOI] [PubMed] [Google Scholar]
  34. Schott M., Schatz D., Atkinson M., Krischer J., Mehta H., Vold B., Maclaren N. GAD65 autoantibodies increase the predictability but not the sensitivity of islet cell and insulin autoantibodies for developing insulin dependent diabetes mellitus. J Autoimmun. 1994 Dec;7(6):865–872. doi: 10.1006/jaut.1994.1070. [DOI] [PubMed] [Google Scholar]
  35. Seissler J., Morgenthaler N. G., Achenbach P., Lampeter E. F., Glawe D., Payton M., Christie M., Scherbaum W. A. Combined screening for autoantibodies to IA-2 and antibodies to glutamic acid decarboxylase in first degree relatives of patients with IDDM. The DENIS Study Group. Deutsche Nikotinamid Interventions-Studie. Diabetologia. 1996 Nov;39(11):1351–1356. doi: 10.1007/s001250050582. [DOI] [PubMed] [Google Scholar]
  36. 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]
  37. Tuomilehto J., Lounamaa R., Tuomilehto-Wolf E., Reunanen A., Virtala E., Kaprio E. A., Akerblom H. K. Epidemiology of childhood diabetes mellitus in Finland--background of a nationwide study of type 1 (insulin-dependent) diabetes mellitus. The Childhood Diabetes in Finland (DiMe) Study Group. Diabetologia. 1992 Jan;35(1):70–76. doi: 10.1007/BF00400854. [DOI] [PubMed] [Google Scholar]
  38. Tuomilehto J., Zimmet P., Mackay I. R., Koskela P., Vidgren G., Toivanen L., Tuomilehto-Wolf E., Kohtamäki K., Stengård J., Rowley M. J. Antibodies to glutamic acid decarboxylase as predictors of insulin-dependent diabetes mellitus before clinical onset of disease. Lancet. 1994 Jun 4;343(8910):1383–1385. doi: 10.1016/s0140-6736(94)92521-6. [DOI] [PubMed] [Google Scholar]
  39. Veijola R., Reijonen H., Vähäsalo P., Sabbah E., Kulmala P., Ilonen J., Akerblom H. K., Knip M. HLA-DQB1-defined genetic susceptibility, beta cell autoimmunity, and metabolic characteristics in familial and nonfamilial insulin-dependent diabetes mellitus. Childhood Diabetes in Finland (DiMe) Study Group. J Clin Invest. 1996 Dec 1;98(11):2489–2495. doi: 10.1172/JCI119067. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Verge C. F., Gianani R., Kawasaki E., Yu L., Pietropaolo M., Jackson R. A., Chase H. P., Eisenbarth G. S. Prediction of type I diabetes in first-degree relatives using a combination of insulin, GAD, and ICA512bdc/IA-2 autoantibodies. Diabetes. 1996 Jul;45(7):926–933. doi: 10.2337/diab.45.7.926. [DOI] [PubMed] [Google Scholar]
  41. Wiest-Ladenburger U., Hartmann R., Hartmann U., Berling K., Böhm B. O., Richter W. Combined analysis and single-step detection of GAD65 and IA2 autoantibodies in IDDM can replace the histochemical islet cell antibody test. Diabetes. 1997 Apr;46(4):565–571. doi: 10.2337/diab.46.4.565. [DOI] [PubMed] [Google Scholar]
  42. Ziegler A. G., Ziegler R., Vardi P., Jackson R. A., Soeldner J. S., Eisenbarth G. S. Life-table analysis of progression to diabetes of anti-insulin autoantibody-positive relatives of individuals with type I diabetes. Diabetes. 1989 Oct;38(10):1320–1325. doi: 10.2337/diab.38.10.1320. [DOI] [PubMed] [Google Scholar]

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