Reviews in Endocrine and Metabolic Disorders

, Volume 4, Issue 3, pp 213–223 | Cite as

Environmental Triggers and Determinants of Beta-Cell Autoimmunity and Type 1 Diabetes

  • Mikael Knip
dietary factors growth viruses toxins standard of hygiene 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Ilonen J, Sjöroos M, Knip M, Veijola R, Simell O, Åkerblom HK, Paschou P, Bozas E, Havarini B, Malamitsi-Puchner A, Thymelli J, Vazeou A, Bartsocas CS. Estimation of genetic risk for type 1 diabetes. Am J Med Genet 2002;115:30–36.Google Scholar
  2. 2.
    Dahlquist G. Environmental risk factors in human type 1 diabetes: An epidemiological perspective. Diabetes Metab Rev 1995;11:37–46.Google Scholar
  3. 3.
    Åkerblom HK, Knip M. Putative environmental factors in type 1 diabetes. Diabetes Metab Rev 1998;14:31–67.Google Scholar
  4. 4.
    Å kerblom HK, Vaarala O, Hyöty H, Ilonen J, Knip M. Environmental factors in the etiology of type 1 diabetes. Am J Med Genet 2002;115:18–29.Google Scholar
  5. 5.
    Barnett AH, Eff C, Leslie RDG, Pyke DA. Diabetes in identical twins. A study of 200 pairs. Diabetologia 1981;20:87–93.Google Scholar
  6. 6.
    Kaprio J, Tuomilehto J, Koskenvuo M, Romanov K, Reunanen A, Eriksson J, Stengård J, Kesäniemi YA. Concordance for Type 1 (insulin-dependent) and Type 2 (non-insulin-dependent) diabetes mellitus in a population-based cohort of twins in Finland. Diabetologia 1992;35:1060–1067.Google Scholar
  7. 7.
    The EURODIAB ACE Study Group. Variation and trends in incidence of childhood diabetes in Europe. Lancet 2000;355:873–876.Google Scholar
  8. 8.
    Gale EA. The rise of childhood type 1 diabetes in the 20th century. Diabetes 2002;51:3353–3361.Google Scholar
  9. 9.
    Yoon JW. Role of viruses in the pathogenesis of IDDM. Ann Med 1991;23:437–445.Google Scholar
  10. 10.
    Szopa TM, Titchener PA, Portwood ND, Taylor KW. Diabetes mellitus due to viruses–some recent developments. Diabetologia 1993;36:687–695.Google Scholar
  11. 11.
    Hyöty H, Taylor KW. The role of viruses in human diabetes. Diabetologia 2002;45:1353–1361.Google Scholar
  12. 12.
    Gamble DR, Taylor KW. Seasonal incidence of diabetes mellitus. Br Med J 1969;3:631–633.Google Scholar
  13. 13.
    Barrett-Connor E. Is insulin-dependent diabetes mellitus caused by Coxsackie B infection? A review of the epidemiologic evidence. Rev Inf Dis 1985;7:207–215.Google Scholar
  14. 14.
    Banatvala JE. Insulin-dependent (juvenile-onset, type 1) diabetes mellitus. Coxsackie B viruses revisited. Prog Med Virol 1987;34: 33–54.Google Scholar
  15. 15.
    Orchard TJ, Atchison RW, Becker D, Rabin B, Eberhardt M, Kuller LH, LaPorte RE, Cavender D. Coxsackie infection and diabetes. Lancet 1983;2:631.Google Scholar
  16. 16.
    Mertens T, Grüneklee D, Eggers HJ. Neutralizing antibodies against Coxsackie B viruses in patients with recent onset of type 1 diabetes. Eur J Pediatr 1983;140:293–294.Google Scholar
  17. 17.
    Palmer JP, Cooney MK, Ward RH, Hansen JA, Brodsky JB, Ray CG, Crossley JR, Asplin CM, Williams RH. Reduced Coxsackie antibody titres in Type 1 (insulin-dependent) diabetic patients presenting during an outbreak of Coxsackie B3 and B4 infection. Diabetologia 1982;22:426–429.Google Scholar
  18. 18.
    Graves PM, Norris JM, Pallansch MA, Gerling IC, Rewers M. The role of enteroviral infections in the development of IDDM: Limitations of current approaches. Diabetes 1997;46:161–168.Google Scholar
  19. 19.
    Frisk G, Fohlman J, Kobbah M, Ewald U, Tuvemo T, Diderholm H, Friman G. High frequency of Coxsackie-B-virus-specific IgM in children developing type 1 diabetes during a period of high diabetes morbidity. J Med Virol 1985;17:219–227.Google Scholar
  20. 20.
    Fohlman J, Friman G. Is juvenile diabetes a viral disease? Ann Med 1993;25:569–574.Google Scholar
  21. 21.
    Nerup J, Mandrup-Poulsen T, Mølvig J, Helqvist S, Wogensen L, Egeberg J. Mechanisms of pancreatic beta-cell destruction in Type 1 diabetes. Diabetes Care 1988;11(Suppl 1):16–23.Google Scholar
  22. 22.
    Dahlquist CG, Ivarsson S, Lindberg B, Forsgren M. Maternal enteroviral infection during pregnancy. Diabetes 1995;44:408–413.Google Scholar
  23. 23.
    Hyöty H, Hiltunen M, Knip M, Laakkonen M, Vähäsalo P, Karjalainen J, Koskela P, Roivainen M, Leinikki P, Hovi T, Åkerblom HK, The Childhood Diabetes in Finland Study Group. Aprospective study of the role of Coxsackie B and other enterovirus infections in the pathogenesis of IDDM. Diabetes 1995;44:652–657.Google Scholar
  24. 24.
    Hiltunen M, Hyöty H, Knip M, Ilonen J, Reijonen H, Vähäsalo P, Roivainen M, Leinikki P, Hovi T, Åkerblom HK, The Childhood Diabetes in Finland Study Group. ICA seroconversion in children is temporally associated with enterovirus infections. J Infect Dis 1997;175:554–560.Google Scholar
  25. 25.
    Clements CB, Galbraith D, Taylor KW. Coxsackie B virus infection and onset of childhood diabetes. Lancet 1995;346:221–223.Google Scholar
  26. 26.
    Andrealotti L, Hober D, Hober-Vandenberghe C, Belaich S, Vantyghem MC, Lefebvre J, Wattre P. Detection of Coxsackie B virus RNA sequences in whole blood samples from adult patients at the onset of type 1 diabetes mellitus. J Med Virol 1997;52:121–127.Google Scholar
  27. 27.
    Yin H, Berg AK, Tuvemo T, Frisk G. Enterovirus RNA is found in peripheral blood mononuclear cells in a majority of type 1 diabetic children at onset. Diabetes 2002;51:1964–1971.Google Scholar
  28. 28.
    Szopa TM, Ward T, Dronfield DM, Portwood ND, Taylor KW. Coxsackie B4 viruses with the potential to damage beta cells of the islets are present in clinical isolates. Diabetologia 1990;33:325–328.Google Scholar
  29. 29.
    Gundersen E. Is diabetes of infectious origin? J Inf Dis 1927;41:197–202.Google Scholar
  30. 30.
    Hyöty H, Hiltunen M, Reunanen A, Leinikki P, Vesikari T, Lounamaa R, Tuomilehto J, Åkerblom HK, The Childhood Diabetes in Finland Study Group. Decline of mumps antibodies in Type 1 (insulin-dependent) diabetic children and a plateau in the rising incidence of Type 1 diabetes after introduction of the mumps-measlesrubella vaccine in Finland. Diabetologia 1993;36:1303–1308.Google Scholar
  31. 31.
    Karounas DG, Wolinsky JS, Thomas JW. Monoclonal antibody to rubella virus capsid recognizes a beta-cell antigen. J Immunol 1993;150:3080–3085.Google Scholar
  32. 32.
    Ward KP, Galloway WH, Auchterlonie IA. Congenital cytomegalovirus infection and diabetes. Lancet 1979;1:497.Google Scholar
  33. 33.
    Ivarsson SA, Lindberg B, Nilsson KO, Ahlfors K, Svanberg L. The prevalence of type 1 diabetes mellitus at follow-up of Swedish infants congenitally infected with cytomegalovirus. Diabetic Med 1993;10:521–523.Google Scholar
  34. 34.
    . Hiltunen M, Hyöty H, Karjalainen J, Leinikki P, Knip M, Lounamaa R, Åkerblom HK. The Childhood Diabetes in Finland Study Group. Serological evaluation of the role of cytomegalovirus in the pathogenesis of IDDM: A prospective study. Diabetologia 1995;38:705–710.Google Scholar
  35. 35.
    Suenaga K, Yoon JW. Association of beta-cell specific expression of endogenous retrovirus with the development of insulitis and diabetes in NOD mice. Diabetes 1988;37:1722–1726.Google Scholar
  36. 36.
    Hao W, Serreze DV, McCulloch DK, Neifing JL, Palmer JP. Insulin (auto) antibodies from humanIDDMcross-react with retroviral antigen p73. J Autoimmun 1993;6:787–798.Google Scholar
  37. 37.
    Honeyman MC, Stone NL, Harrison LC. T-cell epitopes in type 1 diabetes autoantigen tyrosine phosphatase IA-2: Potential for mimicry with rotavirus and other environmental agents. Mol Med 1998;4:231–239.Google Scholar
  38. 38.
    Honeyman MC, Coulson BS, Stone NL, Gellert SA, Goldwater PN, Steele CE, Couper JJ, Tait BD, Colman PG, Harrison LC. Association between rotavirus infection and pancreatic islet autoimmunity in children at risk of developing type 1 diabetes. Diabetes 2000;49:1319–1324.Google Scholar
  39. 39.
    Blomquist M, Juhela S, Erkkilä S, Korhonen S, Simell T, Kupila A, Vaarala O, Simell O, Knip M, Ilonen J. Rotavirus infections and development of diabetes-associated autoantibodies during the first 2 years of life. Clin Exp Immunol 2002;128:511–515.Google Scholar
  40. 40.
    Helgason T, Jonasson MR. Evidence for a food additive as a cause of ketosis-prone diabetes. Lancet 1981;2:716–720.Google Scholar
  41. 41.
    Helgason T, Ewen SWB, Ross IS, Stowers JM. Diabetes produced in mice by smoked/cured mutton. Lancet 1982;2:1017–1022.Google Scholar
  42. 42.
    Scott FW, Trick KD. Dietary modification of spontaneous diabetes in the BB Wistar rat. Proc Canad Fed Biol Soc 1983;26:222.Google Scholar
  43. 43.
    Elliott RB, Martin JM. Dietary protein: A trigger of insulindependent diabetes in the BB rat? Diabetologia 1984;26:297–299.Google Scholar
  44. 44.
    Daneman D, Fishman L, Clarson C, Martin JM. Dietary triggers of insulin-dependent diabetes in the BB rat. Diabetes Res 1987;5:93–97.Google Scholar
  45. 45.
    Coleman DL, Kuzava JE, Leiter EH. Effect of diet on incidence of diabetes in non-obese diabetic mice. Diabetes 19990;39:432–436.Google Scholar
  46. 46.
    Martin JM, Trink B, Daneman D, Dosch H-M, Robinson B. Milk proteins in the etiology of insulin-dependent diabetes mellitus. Ann Med 1991;23:447–452.Google Scholar
  47. 47.
    Scott FW. Cow milk and insulin-dependent diabetes mellitus: Is there a relationship? Am J Clin Nutr 1990;51:489–491.Google Scholar
  48. 48.
    Dahl-Jorgensen K, Joner G, Hanssen KF. Relationship between cow's milk consumption and incidence of IDDM in childhood. Diabetes Care 1991;14:1081–1083.Google Scholar
  49. 49.
    Dahlquist GG, Blom L, Persson L-Å, Sandström AIM, Wall SG. Dietary factors and the risk of developing insulin dependent diabetes in childhood. Br Med J 1990;300:1302–1306.Google Scholar
  50. 50.
    Verge CF, Howard NJ, Irwig L, Simpson JM, Mackerras D, Silink M. Environmental factors in childhood IDDM: A population-based case-control study. Diabetes Care 1994;17:1381–1389.Google Scholar
  51. 51.
    Virtanen SM, Hyppönen E, Lä¨arä E, Vähäsalo P, Kulmala P, Savola K. Räsänen L, Knip M, Åkerblom HK, The Childhood Diabetes in Finland Study Group. Cow's milk consumption, disease associated autoantibodies and Type 1 diabetes mellitus: A follow-up study in siblings of diabetic children. Diabetic Med 1998;15:730–738.Google Scholar
  52. 52.
    Borch-Johnsen K, Joner G, Mandrup-Poulsen T, Christy M, Zachau-Christiansen B, Kastrup K, Nerup J. Relation between breast-feeding and incidence rates of insulin-dependent diabetes mellitus. A hypothesis. Lancet 1984;II:1083–1086.Google Scholar
  53. 53.
    Virtanen SM, Räsänen L, Aro A, Lindström J, Sippola H, Lounamaa R, Toivanen L, Tuomilehto J, Åkerblom HK, The Childhood Diabetes in Finland Study Group. Infant feeding in Finnish children <7 yr of age with newly diagnosed IDDM. Diabetes Care 1991;14:415–417.Google Scholar
  54. 54.
    Virtanen SM, Räsänen L, Aro A, Ylönen K, Lounamaa R, Tuomilehto J, Åkerblom HK, The Childhood Diabetes in Finland Study Group. Feeding in infancy and the risk of Type 1 diabetes mellitus in Finnish children. Diabetic Med 1992;9:815–819.Google Scholar
  55. 55.
    Virtanen SM, Räsänen L, Ylönen K, Aro A, Clayton D, Langholz B, Pitkäniemi J, Savilahti E, Lounamaa R, Tuomilehto J, Åkerblom HK, The Childhood Diabetes in Finland Study Group. Early introduction of dairy products associated with increased risk for insulin-dependent diabetes mellitus in Finnish children. Diabetes 1993;42:1786–1790.Google Scholar
  56. 56.
    Gerstein HM. Cow's milk exposure and Type 1 diabetes mellitus: A critical overview of the clinical literature. Diabetes Care 1994;17:13–19.Google Scholar
  57. 57.
    Norris JM, Scott FW. A meta-analysis of infant diet and insulindependent diabetes mellitus: Do biases play a role. Epidemiology 1996;7:87–92.Google Scholar
  58. 58.
    Norris JM, Beaty B, Klingensmith G, Yu L, Hoffman M, Chase HP, Erlich HA, Hamman RF, Eisenbarth GS, Rewers M. Lack of association between early exposure to cow's milk protein and β-cell autoimmunity. JAMA 1996;276:609–614.Google Scholar
  59. 59.
    Couper JJ, Steele C, Beresford S, Powell T, McCaul K, Pollard A, Gellert S, Tait B, Harrison LC, Colman PG. Lack of association between duration of breast-feeding or introduction of cow's milk and development of islet autoimmunity. Diabetes 1999;48:2145–2149.Google Scholar
  60. 60.
    Hummel M, Fuchtenbush M, Schenker M, Ziegler A-G. No major association of breast-feeding, vaccinations, and childhood viral diseases with early islet autoimmunity in the German BABYDIAB Study. Diabetes Care 2000;23:969–974.Google Scholar
  61. 61.
    Kimpimäki T, Erkkola M, Korhonen S, Kupila A, Virtanen SM, Ilonen J, Simell O, Knip M. Short exclusive breast-feeding predisposes young children with increased genetic risk of Type 1 diabetes to progressive beta-cell autoimmunity. Diabetologia 2001;44:63– 69.Google Scholar
  62. 62.
    Savilahti E, Åkerblom HK, Tainio V-M, Koskimies S. Children with newly diagnosed insulin-dependent diabetes mellitus have increased levels of cow's milk antibodies. Diabetes Res 1988;7:137–140.Google Scholar
  63. 63.
    Savilahti E, S aukkonen TT, Virtala ET, Tuomilehto J, Åkerblom HK, The Childhood Diabetes in Finland Study Group. Increased levels of cow's milk and ß-lactoglobulin antibodies in young children with newly diagnosed IDDM. Diabetes Care 1993;16:984–989.Google Scholar
  64. 64.
    Dahlquist G, Savilahti E, Landin-Olsson M. An increased level of antibodies to beta-lactoglobulin is a risk determinant for early-onset Type 1 (insulin-dependent) diabetes mellitus independent of islet cell antibodies and early introduction of cow's milk. Diabetologia 1992;35:980–984.Google Scholar
  65. 65.
    Saukkonen T, Savilahti E, Vaarala O, Virtala ET, Tuomilehto J, Åkerblom HK, The Childhood Diabetes in Finland Study Group. Children with newly diagnosed IDDM have increased levels of antibodies to bovine serum albumin but not to ovalbumin. Diabetes Care 1994;17:970–976.Google Scholar
  66. 66.
    Karjalainen J, Martin JM, Knip M, Ilonen J, Robinson BH, Savilahti E, Åkerblom HK, Dosch H-M. A bovine albumin peptide as a possible trigger of insulin-dependent diabetes mellitus. N Engl J Med 1992;327:302–307.Google Scholar
  67. 67.
    Elliott RB, Harris DP, Hill JP, Bibby NJ, Wasmuth HE. Type I (insulin-dependent) diabetes mellitus and cow milk: Casein variant consumption. Diabetologia 1999;42:292–296.Google Scholar
  68. 68.
    Vaarala O, Saukkonen T, Savilahti E, Klemola T, Åkerblom HK. Development of immune response to cow's milk proteins in infants receiving cow's milk or hydrolyzed formula. J Allergy Clin Immunol 1995;96:917–923.Google Scholar
  69. 69.
    Paronen J, Klemetti P, Kantele JM, Savilahti E, Perheentupa J, Åkerblom HK, Vaarala O. Glutamate decarboxylase-reactive peripheral blood lymphocytes from patients with IDDM express gutspecific homing receptor ά4ß7-integrin. Diabetes 1997;46:583–588.Google Scholar
  70. 70.
    Vaarala O, Paronen J, Otonkoski T, Åkerblom HK. Cow milk formula feeding induces antibodies to insulin in children–a link between cow milk and insulin-dependent diabetes mellitus. Scand J Immunol 1998;47:131–135.Google Scholar
  71. 71.
    Vaarala O, Knip M, Paronen J, Hämäläinen A-M, Muona P, Väätäinen M, Ilonen J, Simell O, Åkerblom HK. Cow milk formula feeding induces primary immunization to insulin in infants at genetic risk for type 1 diabetes. Diabetes 1999;48:1389–1394.Google Scholar
  72. 72.
    Paronen J, Knip M, Savilahti E, Virtanen SM, Ilonen J, Åkerblom HK, Vaarala O, the Finnish TRIGR Study Group. The effect of cow milk exposure and maternal type 1 diabetes: Cellular and humoral immunization to dietary insulin in infants at genetic risk for Type 1 diabetes. Diabetes 2000;49:1657–1665.Google Scholar
  73. 73.
    Arslanian SA, Becker DJ, Rabin B, Atchison R, Eberhardt M, Cavender D, Dorman J, Drash AL. Correlates of insulin autoantibodies in newly diagnosed children with insulin-dependent diabetes before insulin therapy. Diabetes 1985;32:926–930.Google Scholar
  74. 74.
    Karjalainen J, Knip M, Mustonen A, Ilonen J, Åkerblom HK. Relation between insulin antibody and complement-fixing islet cell antibody at clinical diagnosis of IDDM. Diabetes 1986;35:620–622.Google Scholar
  75. 75.
    Ziegler AG, Hummel M, Schenker M, Bonifacio E. Autoantibody appearance and risk for development of childhood diabetes in offspring of parents with type 1 diabetes: The 2-year analysis of the German BABYDIAB Study. Diabetes 1999;48:460–468.Google Scholar
  76. 76.
    Kimpimäki T, Kupila A, Hämäläinen A-M, Kukko M, Kulmala P, Savola K, Simell T, Muona P, Ilonen J, Simell O, Knip M. The first signs of ß-cell autoimmunity appear in infancy in genetically susceptible children from the general population: The FinnishType 1 Diabetes Prediction and Prevention Study. J Clin Endocrinol Metab 2001;86:4782–4788.Google Scholar
  77. 77.
    Åkerblom HK, S avilahti E, Saukkonen TT, Paganus A, Virtanen SM, Teramo K, Knip M, Ilonen J, Karjalainen J, Vaarala O, Reunanen A. The case for elimination of cow's milk in early infancy in the prevention of Type 1 diabetes: The Finnish experience. Diabetes Metab Rev 1993;9:269–278.Google Scholar
  78. 78.
    Åkerblom HK, Virtanen SM, Hämäläinen AM, Ilonen J, Savilahti E, Vaarala O, Reunanen A, Teramo K, Knip M. Emergence of diabetes associated autoantibodies in the nutritional prevention of IDDM (TRIGR) project. Diabetes 1999;48(Suppl 1):A45.Google Scholar
  79. 79.
    Scott FW, Sarwar G, Cloutier HE. Diabetogenicity of various protein sources in the diet of the diabetes-prone BB rat. In: Camerini-Davolos RA, Cole HS, eds. Prediabetes, New York: Plenum Press, 1988:277–285.Google Scholar
  80. 80.
    Atkinson MA, Winter WE, Skordis N, Beppu H, Riley WM, MacLaren NK. Dietary protein restriction reduces the frequency and delays the onset of insulin dependent diabetes in BB rats. Autoimmunity 1988;2:11–220.Google Scholar
  81. 81.
    Hoorfar J, Scott FW, Cloutier HE. Dietary plant materials and development of diabetes in the BB rat. J Nutr 1991;121:908–916.Google Scholar
  82. 82.
    Fort P, Lanes R, Dahlem S, Recker B, Weyman-Daum M, Pugliese M, Lifshitz F. Breast feeding and insulin-dependent diabetes mellitus in children. J Am Coll Nutr 1986;5:439–441.Google Scholar
  83. 83.
    MacFarlane AJ, B urghardt KM, Kelly J, S imell T, Simell O, Altosaar I, Scott FW. A type 1 diabetes-related protein from wheat (Triticum aestivum). A cDNA clone of a wheat storage globulin, Glb1, linked to islet damage. J Biol Chem 2003;278:54–63.Google Scholar
  84. 84.
    Tuomilehto J, T uomilehto-Wolf E, Virtala E, LaPorte R. Coffee consumption as trigger for insulin dependent diabetes mellitus in childhood. Br Med J 1990;300:642–643.Google Scholar
  85. 85.
    Soltesz G, Jeges S, Dahlquist G, Hungarian Childhood Diabetes Epidemiology Study Group. Non-genetic risk determinants for type 1 (insulin-dependent) diabetes mellitus in childhood. Acta Paediatr 1994;83:730–735.Google Scholar
  86. 86.
    Virtanen SM, Räsänen L, Aro A, Ylönen K, Lounamaa R, Åkerblom HK, Tuomilehto J, The Childhood Diabetes in Finland Study Group: Is children's or parents' coffee or tea consumption associated with the risk for type 1 diabetes mellitus in children? Eur J Clin Nutr 1994;48:279–285.Google Scholar
  87. 87.
    Haglund B, Ryckenberg K, Selinus O, Dahlquist G. Evidence of a relationship between childhood-onset Type 1 diabetes and low groundwater concentration of zinc. Diabetes Care 1996;19:873– 875.Google Scholar
  88. 88.
    The EURODIAB Substudy 2 Study Group. Vitamin D supplement in early childhood and risk of Type I (insulin-dependent) diabetes mellitus. Diabetologia 1999;42:51–54.Google Scholar
  89. 89.
    Hyppönen E, Läärä E, Järvelin MR, Virtanen SM. Intake of vitamin D and risk of Type 1 diabetes: A birth cohort study. Lancet 2001;358:1500–1504.Google Scholar
  90. 90.
    Fournier C, Gepner P, Sadouk M, Charriere J. In vivo beneficial effects of cyclosporin A and 1,25-dihydroxyvitamin D3 on the induction of experimental autoimmune thyroiditis. Clin Immunol Immunopathol 1990;54:53–63.Google Scholar
  91. 91.
    Mathieu C, Waer M, Laureys J, Rutgeerts O, Nouillon R. Prevention of type 1 diabetes in NOD mice by 1,25-dihydoxyvitamin D3. Diabetologia 1994;37:552–558.Google Scholar
  92. 92.
    Myers MA, Mackay IR, Rowley MJ, Zimmet PZ. Dietary microbial toxins and type 1 diabetes—a new meaning for seed and soil. Diabetologia 2001;44:1199–1200.Google Scholar
  93. 93.
    Hyppönen E, Kenward MG, Virtanen SM, Piitulainen A, Virta-Autio P, Knip M, Åkerblom HK, The Childhood Diabetes in Finland Study Group. Infant feeding, early weight gain and risk of type 1 diabetes. Diabetes Care 1999;22:1961–1965.Google Scholar
  94. 94.
    Hyppönen E, Virtanen SM, Kenward MG, Knip M, Åkerblom HK, The Childhood Diabetes in Finland Study Group: Obesity, increased linear growth and risk of type 1 diabetes mellitus in children. Diabetes Care 2000;23:1755–1760.Google Scholar
  95. 95.
    Wilkin TJ. The accelerator hypothesis: Weight gain as the missing link between type 1 and type 2 diabetes. Diabetologia 2001;44:914– 922.Google Scholar
  96. 96.
    Knip M. Natural course of preclinical type 1 diabetes. Horm Res 2002;57(Suppl 1):6–11.Google Scholar
  97. 97.
    The EURODIABACE Study Group and the EURODIABACE Substudy 2 Study Group. Familial risk of type 1 diabetes in European children. Diabetologia 1998;41:1151–1156.Google Scholar
  98. 98.
    Bingley PJ, Christie MR, Bonifacio E, Bonfanti R, Shattock M, Fonte MT, Bottazzo GF, Gale EAM. Combined analysis of autoantibodies improves prediction of IDDM in islet cell antibody-positive relatives. Diabetes 1994;43:1304–1310.Google Scholar
  99. 99.
    Kulmala P, Petersen JS, Vähäsalo P, Karjalainen J, Löppönen T, Dyrberg T, Åkerblom HK, Knip M, The Childhood Diabetes in Finland Study Group. Prediction of insulin-dependent diabetes mellitus in siblings of diabetic children–a population-based study. J Clin Invest 1998;101:327–336.Google Scholar

Copyright information

© Kluwer Academic Publishers 2003

Authors and Affiliations

  • Mikael Knip
    • 1
    • 2
  1. 1.Hospital for Children and AdolescentsUniversity of HelsinkiHelsinki
  2. 2.Department of PediatricsTampere University HospitalTampereFinland

Personalised recommendations