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Autoimmunity and familial risk of type 1 diabetes

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Abstract

There is evidence that the process leading to type 1 diabetes may start in early infancy or already in utero. Even though diabetes-associated antibodies can be detected in up to half of the pregnancies of mothers with type 1 diabetes, pregnancy itself has no major effect on these antibodies. If such antibodies are present in the mother, they are transferred to the fetal circulation and are detectable in cord blood. Most of the transplacentally transferred antibodies disappear by 6 months of age, but may persist even longer. Antibodies present in cord blood may represent true induction of β-cell autoimmunity, but such a phenomenon is extremely rare.

The offspring of affected mothers have a 2% to 3% risk of type 1 diabetes, which is about one third of that in the offspring of affected fathers. A novel conceivable explanation is that exogenous insulin transplacentally transferred in immune complexes might lead to the induction of tolerance to insulin, which may be the primary autoantigen in type 1 diabetes. The possible protective or predisposing effect of diabetes-associated antibodies detectable at birth on progression to clinical type 1 diabetes later will be assessed in ongoing prospective birth cohort studies.

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References and Recommended Reading

  1. Gorsuch AN, Lister J, Dean BM, et al.: Evidence for a long prediabetic period in type 1 (insulin-dependent) diabetes mellitus. Lancet 1981, 2:1363–1365.

    Article  PubMed  CAS  Google Scholar 

  2. Eisenbarth GS: Type 1 diabetes mellitus, a chronic autoimmune disease. N Engl J Med 1986, 314:1360–1368.

    Article  PubMed  CAS  Google Scholar 

  3. Akerblom HK, Knip M: Putative environmental risk factors in type 1 diabetes. Diabetes Metab Rev 1998, 14:31–67.

    PubMed  CAS  Google Scholar 

  4. Dahlquist GG, Ivarsson S, Lindberg B, Forsgren M: Maternal enteroviral infection during pregnancy as a risk factor for childhood IDDM. A population-based case-control study. Diabetes 1995, 44:408–413.

    Article  PubMed  CAS  Google Scholar 

  5. Hyöty H, Hiltunen M, Knip M, et al.: A prospective study of the role of Coxsackie B and other enterovirus infections in the pathogenesis of IDDM. Diabetes 1995, 44:652–657.

    Article  PubMed  Google Scholar 

  6. Otonkoski T, Roivainen M, Vaarala O, et al.: Neonatal type 1 diabetes associated with maternal echovirus 6 infection: a case report. Diabetologia 2000, 43:1235–1238.

    Article  PubMed  CAS  Google Scholar 

  7. Hummel M, Ziegler AG, Lewy H, et al.: IAA/GAD-positive offspring of diabetic parents have a different seasonality in month of birth than antibody-negative offspring. Diabetes Care 2001, 11:2001.

    Article  Google Scholar 

  8. Knip M, Kukko M, Kulmala P, et al.: Humoral beta-cell autoimmunity in relation to HLA-defined disease susceptibility in preclinical and clinical type 1 diabetes. Am J Med Genet 2002, in press.

  9. Kimpimäki T, Knip M: Disease-associated autoantibodies as predictive markers of type 1 diabetes mellitus in siblings of affected children. J Pediatr Endocrinol Metab 2001, 14:575–587.

    PubMed  Google Scholar 

  10. Petersen JS, Kyvik KO, Bingley PJ: Population based study of prevalence of islet cell autoantibodies in monozygotic and dizygotic Danish twin pairs with insulin dependent diabetes mellitus. BMJ 1997, 314:1575–1579.

    PubMed  CAS  Google Scholar 

  11. Mylvaganam R, Stowers JM, Steel JM, et al.: Insulin immunogenity in pregnancy: maternal and fetal studies. Diabetologia 1983, 24:19–25.

    Article  PubMed  CAS  Google Scholar 

  12. Di Mario U, Fallucca F, Gargiulo P, et al.: Insulin-anti-insulin complexes in diabetic women and their neonates. Diabetologia 1984, 27:83–86.

    Article  PubMed  Google Scholar 

  13. Exon PD, Dixon K, Malins JM: Insulin antibodies in diabetic pregnancy. Lancet 1974, 1:126–128.

    Article  Google Scholar 

  14. Dozio N, Beretta A, Castiglioni M, et al.: Insulin antibodies do not preclude optimization of metabolic control in women with IDDM during pregnancy. Diabetes Care 1996, 19:979–982.

    Article  PubMed  CAS  Google Scholar 

  15. Ziegler A-G, Hillebrand B, Rabl W, et al.: On the appearance of islet associated autoimmunity in offspring of diabetic mothers: a prospective study from birth. Diabetologia 1993, 36:402–408.

    Article  PubMed  CAS  Google Scholar 

  16. Martikainen A, Saukkonen T, Kulmala PK, et al.: Disease-associated antibodies in offspring of mothers with IDDM. Diabetes 1996, 45:1706–1710.

    Article  PubMed  CAS  Google Scholar 

  17. Weiss PAM, Kainer F, Pürstner P, et al.: Anti-insulin antibodies and birth weight in pregnancies complicated by diabetes. Early Hum Develop 1998, 53:145–154.

    Article  CAS  Google Scholar 

  18. Roll U, Christie MR, Fuchtenbusch M, et al.: The German multicenter BABY-DIAB study: detection of humoral immune responses to islet antigens in early childhood. Diabetes 1996, 45:967–973.

    Article  PubMed  Google Scholar 

  19. Hämäläinen A-M, Savola K, Kulmala PK, et al.: Disease-associated autoantibodies during pregnancy and at birth in families affected by type 1 diabetes. Clin Exp Immunol 2001, 126:230–235.

    Article  PubMed  Google Scholar 

  20. Wegmann TG, Lin H, Guilbert L, Mosmann TR: Bidirectional cytokine interactions in the maternal-fetal relationship: is successful pregnancy a Th2 phenomenon? Immunol Today 1993, 14:353–356.

    Article  PubMed  CAS  Google Scholar 

  21. Lernmark Å: Molecular biology of IDDM. Diabetologia 1994, 37:S73-S81.

    Article  PubMed  Google Scholar 

  22. Leiper JM, Fineberg SE, Lunan CB, MacCuish AC: Insulin antibodies in the maternal and fetal circulation of pregnant diabetic women treated with human insulin or recombinant DNA origin. Diabetes Res 1984, 1:75–81.

    PubMed  CAS  Google Scholar 

  23. Tingle AJ, Lim G, Wright VJ, et al.: Transplacental passage of islet cell antibody in infants of diabetic mothers. Pediatr Res 1979, 13:1323–1325.

    Article  PubMed  CAS  Google Scholar 

  24. Hämäläinen A-M, Ilonen J, Simell O, et al.: Prevalence and fate of type 1 diabetes-associated autoantibodies in cord blood samples from newborn infants of non-diabetic mothers. Diabetes Metab Res Rev 2002, 18:57–63.

    Article  PubMed  Google Scholar 

  25. Spellacy WN, Goetz FC: Insulin antibodies in pregnancy. Lancet 1963, 1:222–224.

    Article  Google Scholar 

  26. Hämäläinen A-M, Ronkainen MS, Åkerblom HK, Knip M: Postnatal elimination of transplacentally acquired disease-associated antibodies in infants born to families with type 1 diabetes. J Clin Endocrinol Metab 2000, 85:4249–4253. The elimination of transplacentally transferred antibodies is demonstrated.

    Article  PubMed  Google Scholar 

  27. Corrado MC, Bosco A, Moretti C, et al.: Congenital autoimmune diabetes mellitus. N Engl J Med 2000, 342:1529–1531.

    Article  Google Scholar 

  28. Ziegler A-G, Hummel M, Schenker M, Bonifacio E: Autoantibody appearance and risk for development of childhood diabetes in offspring of parents with type 1 diabetes. Diabetes 1999, 48:460–468. A large cohort of infants from diabetic families is followed for the appearance of autoantibodies.

    Article  PubMed  CAS  Google Scholar 

  29. Lindberg B, Ivarsson S-A, Landin-Olsson M, et al.: Islet autoantibodies in cord blood from children who developed type 1 (insulin-dependent) diabetes mellitus before 15 years of age. Diabetologia 1999, 42:181–187.

    Article  PubMed  CAS  Google Scholar 

  30. Mitchell ML, Quinn M, Orban T, Hermos RJ: Failure to find GAD antibodies at birth in children with diabetes. Diabetes Care 1998, 21:197–198.

    PubMed  CAS  Google Scholar 

  31. Ivarsson S-A, Ackerfors M, Carlsson A, et al.: Glutamate decarboxylase antibodies in non-diabetic pregnancy precedes insulin-dependent diabetes in the mother but not necessarily in the offspring. Autoimmunity 1997, 26:261–269.

    Article  PubMed  CAS  Google Scholar 

  32. Naserke HE, Bonifacio E, Ziegler A-G: Prevalence, characteristics and diabetes risk associated with transient maternally acquired islet antibodies and persistent islet antibodies in offspring of parents with type 1 diabetes. J Clin Endocrinol Metab 2001, 86:4826–4833. The distinguishing of maternal antibodies from autoantibodies in infants under the age of 1 year in a large cohort study. It poses the question, "How do you evaluate the risk of type 1 diabetes in the autoantibody-positive infant?".

    Article  PubMed  CAS  Google Scholar 

  33. Yu J, Yu L, Bugawan TL, et al.: Transient anti-islet autoantibodies: infrequent occurrence and lack of association with "genetic risk factors." J Clin Endocrinol Metab 2000, 85:2421–2428.

    Article  PubMed  CAS  Google Scholar 

  34. Colman PG, Steele C, Couper JJ, et al.: Islet autoimmunity in infants with type 1 diabetic relative is common but frequently restricted to one autoantibody. Diabetologia 2000, 43:203–209.

    Article  PubMed  CAS  Google Scholar 

  35. Kimpimäki T, Kupila A, Hämäläinen A-M, et al.: The first signs of beta-cell autoimmunity appear in infancy in genetically susceptible children from the general population: the Finnish type 1 diabetes prediction and prevention study. J Clin Endocrinol Metab 2001, 86:4782–4788.

    Article  PubMed  Google Scholar 

  36. Plagemann A, Harder T, Kohlhoff R, et al.: Glucose tolerance and insulin secretion in children of mothers with pregestational IDDM or gestational diabetes. Diabetologia 1997, 40:1094–1100.

    Article  PubMed  CAS  Google Scholar 

  37. Weiss AM, Scholz HS, Haas J, et al.: Long term follow-up of infants of mothers with type 1 diabetes. Diabetes Care 2000, 23:905–911.

    Article  PubMed  CAS  Google Scholar 

  38. Warram JH, Krolewski AS, Gottlieb MS, Kahn CR: Differences in risk of insulin-dependent diabetes in offspring of diabetic mothers and fathers. N Engl J Med 1984, 311:149–152.

    Article  PubMed  CAS  Google Scholar 

  39. Warram JH, Martin BC, Krolewski AS: Risk of IDDM in children of diabetic mothers decrease with increasing maternal age at pregnancy. Diabetes 1991, 40:1679–1684.

    Article  PubMed  CAS  Google Scholar 

  40. Tuomilehto J, Lounamaa R, Tuomilehto-Wolf E, et al.: Epidemiology of childhood diabetes mellitus in Finland—background of a nationwide study of type 1 (insulin-dependent) diabetes mellitus. Diabetologia 1992, 35:70–76.

    Article  PubMed  CAS  Google Scholar 

  41. Warram JH, Krolewski AS, Kahn CR: Determinants of IDDM and perinatal mortality in children of diabetic mothers. Diabetes 1988, 37:1328–1334.

    Article  PubMed  CAS  Google Scholar 

  42. Buschard K, Kuhl C, Molsted-Pedersen L, et al.: Investigations in children who were in utero at onset of insulin-dependent diabetes in their mothers. Lancet 1989, 1:811–814.

    Article  PubMed  CAS  Google Scholar 

  43. Pack CD, Cestra AE, Min B, et al.: Neonatal exposure to antigen primes the immune system to develop responses to various lymphoid organs and promotes bystander regulation of diverse T cell specifities. J Immunol 2001, 167:4187–4195.

    PubMed  CAS  Google Scholar 

  44. Paronen J, Knip M, Savilahti E, et al.: Effect of cow's milk exposure and maternal type 1 diabetes on cellular and humoral immunization to dietary insulin in infants at genetic risk for type 1 diabetes. Diabetes 2000, 49:1657–1665.

    Article  PubMed  CAS  Google Scholar 

  45. Yu L, Chase HP, Falorni A, et al.: Sexual dimorphism in transmission of expression of islet autoantibodies to offspring. Diabetologia 1995, 38:1353–1357.

    PubMed  CAS  Google Scholar 

  46. Mauricio D, de Leiva A: Autoimmune gestational diabetes mellitus: a distinct clinical entity? Diabetes Metab Res Rev 2001, 17:422–428.

    Article  PubMed  CAS  Google Scholar 

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Hämäläinen, AM., Knip, M. Autoimmunity and familial risk of type 1 diabetes. Curr Diab Rep 2, 347–353 (2002). https://doi.org/10.1007/s11892-002-0025-2

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