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Kinder- und Jugendmedizin 2005; 5(04): 184-191
DOI: 10.1055/s-0037-1617864
Diabetes
Schattauer GmbH

Ätiopathogenese des Typ-1-Diabetes mellitus

Aetiopathogenesis of type 1 diabetes mellitus
Klemens Raile
1   Universitätsklinik für Kinder und Jugendliche Leipzig (Direktor: Prof. Dr. med. W. Kiess)
,
Thomas M. Kapellen
1   Universitätsklinik für Kinder und Jugendliche Leipzig (Direktor: Prof. Dr. med. W. Kiess)
,
Angela Galler
1   Universitätsklinik für Kinder und Jugendliche Leipzig (Direktor: Prof. Dr. med. W. Kiess)
,
Wieland Kiess
1   Universitätsklinik für Kinder und Jugendliche Leipzig (Direktor: Prof. Dr. med. W. Kiess)
› Author Affiliations
Further Information

Publication History

Eingegangen: 09 July 2004

angenommen: 16 February 2005

Publication Date:
11 January 2018 (online)

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Zusammenfassung

Der Diabetes mellitus Typ 1 ist eine durch Umweltfaktoren ausgelöste Autoimmunerkrankung, die genetisch empfängliche Personen trifft. Begünstigende Umweltfaktoren sind Nahrungsmittel, wie Kuhmilchprotein, virale Infekte und unterschiedliche Umweltgifte, wie Nitrosamine. Typ-1-Diabetes wird als zellvermittelte Autoimmunerkrankung mit progressiver Zerstörung der insulinproduzierenden Beta-Zellen verstanden. Dabei spielt die Aktivierung proapoptotischer Signalwege (programmierter Zelltod) durch inflammatorische Zytokine eine Schlüsselrolle beim Zelltod der β-Zellen. Den T-Lymphozyten vom so genannten Helfer-Typ (Th1) wird dabei eine zentrale Rolle zugeschrieben. Zytokine, die überwiegend von Th1-Zellen sezerniert werden, sind Interleukin-1 (IL-1)β, Interferon (IFN)-γ und Tumor-Nekrose-Faktor (TNF)α. Die Produktion dieser proinflammatorischen Zytokine wird einer Störung im fein abgestimmten Gleichgewicht zwischen Th1- und Th2-Helfer-T-Zellen zugeschrieben und führt zu einer selektiven Aktivierung von Beta-Zell-spezifischen, zytotoxischen Effektor-T-Zellen. Durch eine weitere Aufschlüsselung der Ätiopathogenese des Typ-1-Diabetes mellitus sollen neue Strategien in dessen Prävention und Heilung entwickelt werden.

Summary

Type 1 diabetes mellitus results from a progressive loss of pancreatic beta cell number. Environmental factors such as exposure to cow’s milk protein, viral infections and toxins such as nitrosamines are thought to play a pivotal role in the development of type 1 diabetes by influencing the penetrance of diabetes susceptibility genes. The local production of cytokines such as tumour necrosis factor-alpha (TNFα), interleukin-1 beta (Il-1β) and the synthesis of nitric oxide (NO) are known to induce programmed cell death of pancreatic beta cells. The molecular mechanisms and the cell’s machinery leading to and enhancing apoptosis/programmed cell death have been elucidated. The production of pro-inflammatory cytokines is thought to be a consequence of the disruption of the finely tuned immune balance of Th1-helper and Th2-helper T lymphocytes. This derangement of the immune system leads to the selective activation of beta-cell-cytotoxic effector T cells. It is hoped that the knowledge of the aetiopathogenesis of type 1 diabetes will help to further develop strategies to prevent and ultimately cure the disease.

Schlüsselwörter

Diabetes mellitus Typ 1 - Autoimmunerkrankung - Umweltfaktoren - Apoptose - Zytokine - Th1/Th2-Immunität

Keywords

Type 1 diabetes mellitus - autoimmune disease - environmental factors - apoptosis - cytokines - Th1-helper cells - Th2-helper cells
 

  • Literatur

  • 1 Allen C, Palta M, D’Alessio DJ. Risk of diabetes in siblings and other relatives of IDDM subjects. Diabetes 1991; 40: 831-6.
    CrossrefPubMedSearch in Google Scholar
  • 2 Allison J, Campbell LL, Morahan G. Diabetes in transgenic mice resulting from overexpression of class J histocompatibility molecules in pancreatic beta cells. Nature 1988; 333: 52933.
    Search in Google Scholar
  • 3 Berardinis de P, Londei M, James REL. Do CD4positive cytotoxic T cells damage islet beta cells in type 1 diabetes?. Lancet 1988; 1: 823-4.
    PubMedSearch in Google Scholar
  • 4 Betterle C, Magrin L, Presotto F. Insulin autoantibodies as markers of potential diabetes mellitus. Lancet 1989; 1: 223-4.
    PubMedSearch in Google Scholar
  • 5 Blom L, Persson LA, Dahlquist G. A high linear growth is associated with an increased risk of childhood diabetes mellitus. Diabetologia 1992; 35: 528-33.
    CrossrefPubMedSearch in Google Scholar
  • 6 Bottino R, Lemarchand P, Trucco M, Giannoukakis N. Gene- and cell-based therapeutics for type 1 diabetes mellitus. Gene Ther 2003; 10: 875-89.
    CrossrefPubMedSearch in Google Scholar
  • 7 Dahlquist G, Blom L, Holmgren G, Hagglof B, Larsson Y, Sterky G, Wall S. The epidemiology of diabetes in Swedish children 0–14 years – a sixyear prospective study. Diabetologia 1985; 28: 802-8.
    CrossrefPubMedSearch in Google Scholar
  • 8 DeStefano F, Mullooly JP, Okoro CA, Chen RT, Marcy SM, Ward JI, Vadheim CM, Black SB, Shinefield HR, Davis RL, Bohlke K. Vaccine Safety Datalink Team. Childhood vaccinations, vaccination timing, and risk of type 1 diabetes mellitus. Pediatrics 2001; 108: E112.
    CrossrefPubMedSearch in Google Scholar
  • 9 Donath MY, Gross DJ, Cerasi E, Kaiser N. Hyperglycemia-induced beta-cell apoptosis in pancreatic islets of psammomys obesus during development of diabetes. Diabetes 1999; 48: 738-44.
    CrossrefPubMedSearch in Google Scholar
  • 10 EURODIAB Substudy 2 Study Group. Infections and vaccinations as risk factors for childhood type I (insulin-dependent) diabetes mellitus: a multicentre case-control investigation. Diabetologia 2000; 43: 47-53.
    CrossrefPubMedSearch in Google Scholar
  • 11 Gallaher B, Hille R, Raile K, Kiess W. Apoptosis: to die or to survive – both is hard work. Horm Metab 2001; 33: 511-9.
    Search in Google Scholar
  • 12 Gerstein HC. Cow’s milk exposure and type 1 diabetes mellitus: a critical overview of the literature. Diabetes Care 1994; 17: 13-9.
    CrossrefPubMedSearch in Google Scholar
  • 13 Guberski DL, Thomas VA, Shek WR. Induction of type I diabetes by Kilhams rat virus in diabetes resistant BB/Wor rats. Science 1991; 254: 1010-3.
    CrossrefPubMedSearch in Google Scholar
  • 14 Hagloof B, Blom L, Dahlquits G, Lonnberg G, Sahlin B. The Swedish childhood diabetes study: indications of sever psychological stress as a risk factor for type 1 diabetes mellitus in childhood. Diabetologia 1991; 34: 579-83.
    CrossrefPubMedSearch in Google Scholar
  • 15 Hermann R, Knip M, Veijola R, Simell O, Laine AP, Akerblom HK, Groop PH, Forsblom C, Pettersson-Fernholm K, Ilonen J. Temporal changes in the frequencies of HLA genotypes in patients with Type 1 diabetes-indication of an increased environmental pressure?. Diabetologia 2003; 46: 420-5.
    CrossrefPubMedSearch in Google Scholar
  • 16 Ho E, Bray TM. Antioxidants, NFKappaB activation and diabetogenesis. Proc Soc Exp Biol Med 1999; 222: 205-13.
    CrossrefPubMedSearch in Google Scholar
  • 17 Hogg J, Hill DJ, Han VKM. The ontogeny of IGF and IGFBP gene expression in the rat pancreas. J Mol Endocrinol 1994; 13: 49-58.
    CrossrefPubMedSearch in Google Scholar
  • 18 Huck C, Endl J, Walk T, Noessner E, Jung G, Wank R, Schendel DJ. HLA-DR53 molecules restrict glutamic acid decarboxylase peptide presentation to T cells of a type 1 diabetes patient: specification of the trimolecular HLA-peptide/T-cell receptor complex. Diabetologia 2001; 44: 70-80.
    CrossrefPubMedSearch in Google Scholar
  • 19 Hummel M, Füchtenbusch M, Schenker M, Ziegler AG. No major association of breast-feeding, vaccinations, and childhood viral diseases with early onset islet autoimmunity in the German BABYDIAB study. Diabetes Care 2000; 23: 969-74.
    CrossrefPubMedSearch in Google Scholar
  • 20 Johansson C, Samuelsson U, Ludvigsson J. A high weight gain early in life is associated with an increased risk of type 1 (insulin-dependent) diabetes mellitus. Diabetologia 1994; 37: 91-4.
    CrossrefPubMedSearch in Google Scholar
  • 21 Jones DB, Hunter NRJ, Duff GW. Heatshock protein 65 as a betacell antigen of insulin dependent diabetes. Lancet 1990; 336: 583-5.
    CrossrefPubMedSearch in Google Scholar
  • 22 Jun HS, Yoon JW. The role of viruses in Type I diabetes: two distinct cellular and pathogenic mechanisms of virus-induced diabetes in animals. Diabetologia 2001; 44: 271-85.
    CrossrefPubMedSearch in Google Scholar
  • 23 Kimpimäki T, Erkkola M, Kothonen S, Kupila A, Virtanen SM, Ilonen J, Simell O, Knip M. Shortterm exclusive breast-feeding predisposes young children with increased genetic risk of Type 1 diabetes to grogressive beta-cell autoimmunity. Diabetologia 2001; 44: 63-9.
    CrossrefPubMedSearch in Google Scholar
  • 24 Kiess W, Kapellen TM, Galler A, Schmidt A, Raile K. Diabetes mellitus: Ätiopathogenese des Diabetes mellitus Typ 1. Monatsschr Kinderheilkd 2001; 149: 641-9.
    CrossrefSearch in Google Scholar
  • 25 Kiess W. Diabetes mellitus im Kindesalter. In: Kruse K. (Hrsg). Pädiatrische Endokrinologie. Stuttgart: Thieme Verlag; 1999: 271-310.
    Search in Google Scholar
  • 26 Kolb H. Ätiopathogenese und Genetik. In: Berger M. (Hrsg). Diabetes mellitus. München: Urban & Schwarzenberg; 1995: 209-14.
    Search in Google Scholar
  • 27 Komulainen J, Kulmala P, Savola K, Lounamaa R, Ilonen J, Reijonen H, Knip M. Clinical, autoimmune, and genetic characteristics of very young children with type 1 diabetes. Diabetes Care 1999; 22: 1950-5.
    CrossrefPubMedSearch in Google Scholar
  • 28 Kukreja A, Maclaren NK. Autoimmunity and diabetes. J Clin Endocrinol Metab 1999; 84: 4371-8.
    CrossrefPubMedSearch in Google Scholar
  • 29 Kupila A, Muona P, Simell T, Arvilommi P, Savolainen H, Hämäläinen AM, Korhonen S, Kimpimäki T, Sjöroos M, Ilonen J, Knip M, Simell O. Feasibility of genetic and immunological prediction of type 1 diabetes in a population-based birth cohort. Diabetologia 2001; 44: 290-7.
    CrossrefPubMedSearch in Google Scholar
  • 30 Kurrer MO, Pakala SV, Hanson HL, Katz JD. Beta-cell apoptosis in T-cell-mediated autoimmune diabetes. Proc Natl Acad Sci USA 1997; 94: 213-8.
    CrossrefPubMedSearch in Google Scholar
  • 31 Lally FJ, Ratcliff H, Bone AJ. Apoptosis and disease progression in the spontaneously diabetic BB/S rat. Diabetologia 2001; 44: 320-4.
    CrossrefPubMedSearch in Google Scholar
  • 32 Lohmann T, Laue S, Nietzschmann U, Kapellen TM, Lehmann I, Schroeder S, Paschke R, Kiess W. Reduced expression of Th1-associated chemokine receptors on peripheral blood lymphocytes at diagnosis of type 1 diabetes. Diabetes 2002; 51: 2474-80.
    CrossrefPubMedSearch in Google Scholar
  • 33 Loweth AC, Williams GT, James RF, Scarpello HJ, Morgan NG. Human islets of Langerhans express FAS ligand and undergo apoptosis in response to IL-1beta and FAS ligand. Diabetes 1998; 47: 727-32.
    CrossrefPubMedSearch in Google Scholar
  • 34 Mandrup-Poulsen T, Nerup J. The autoimmune hypothesis of insulin-dependent diabetes: 1965 to the present. In: Autoimmunity and the pathogenesis of diabetes. Ginsberg Fellner F, McEvoy RC. (Hrsg). Heidelberg: Springer Verlag; 1990
    Search in Google Scholar
  • 35 Mattila PS, Tarkkanen J, Saxen H, Pitkaniemi J, Karvonen M, Tuomilehto J. Predisposition to atopic symptoms to inhaled antigens may protect from childhood type 1 diabetes. Diabetes Care 2002; 25: 865-8.
    CrossrefPubMedSearch in Google Scholar
  • 36 Moriwaki M, Itoh N, Miyagawa J, Yamamoto K, Imagawa A, Yamagata K, Iwahashi H, Nakajima H, Namba M, Nagata S, Hanfusa T, Matzusawa Y. Fas and fas ligand expression in inflamed islets in pancreas sections from patients with recent-onset type 1 diabetes mellitus. Diabetologia 1999; 42: 1332-40.
    CrossrefPubMedSearch in Google Scholar
  • 37 Olmos P, A’LHern R, Heaton DA, Millward BA, Risley D, Pyke DA, Leslie RDG. The significance of the concordance rate for type I (insulin dependent) diabetes in identical twins. Diabetologia 1988; 31: 74750.
    Search in Google Scholar
  • 38 Pakala SV, Kurrer MO, Katz JD. T helper 2 (Th2) cells induce acute pancreatitis and diabetes in immune-compromised nonobese diabetic (NOD) mice. J Exp Med 1997; 186: 299-306.
    CrossrefPubMedSearch in Google Scholar
  • 39 Patterson CC, Dahlquist G, Soltesz G. EURODIAB Substudy 2 Study Group. Maternal age and risk of type 1 diabetes in children. Relative risks by maternal age are biased. BMJ 2001; 322: 1489-90.
    CrossrefPubMedSearch in Google Scholar
  • 40 Rabionovitch A, Suerez-Pinzon W, Strynadka K, Ju Q, Edelstein D, Bownlee M, Korbutt GS, Rojotte RV. Transfection of human pancreatic islets with an anti-apoptotic gene (bcl-2) protects beta-cells from cytokine-induced destruction. Diabetes 1999; 48: 1223-9.
    CrossrefPubMedSearch in Google Scholar
  • 41 Raile K, Berthold A, Banning U. et al. IGFs, basic FGF, and glucose modulate proliferation and apoptosis induced by IFNγ but not by IL-1β in rat INS-1E β-cells. Horm Metab Res 2003; 35: 407-14.
    Thieme ConnectPubMedSearch in Google Scholar
  • 42 Redondo MJ, Yu L, Hawa M, Mackenzie T, Pyke DA, Eisenbarth GS, Leslie RDG. Heterogeneity of type 1 diabetes: analysis of monozygotic twins in Great Britain and the United States. Diabetologia 2001; 44: 354-62.
    CrossrefPubMedSearch in Google Scholar
  • 43 Rose NR, Mackay IR. Molecular mimicry: a critical look at exemplary instances in human diseases. Cell Mol Life Sci 2000; 57: 542-51.
    CrossrefPubMedSearch in Google Scholar
  • 44 Sabbah E, Savola K, Ebeling T, Kulmala P, Vahasalo P, Ilonen J, Salmela PI, Knip M. Genetic, autoimmune, and clinical characteristics of childhood-and adult-onset type 1 diabetes. Diabetes Care 2000; 23: 1326-32.
    CrossrefPubMedSearch in Google Scholar
  • 45 Stene LC, Nafstad P. Relation between occurrence of type 1 diabetes and asthma. Lancet 2001; 357: 607-8.
    CrossrefPubMedSearch in Google Scholar
  • 46 Thornson G, Robinson WP, Kuhner MK. Genetic heterogeneity, modes of inheritance, and risk estimates for a joint study of Caucasians with insulindependent diabetes mellitus. Am J Hum Genet 1988; 43: 799-816.
    PubMedSearch in Google Scholar
  • 47 Todd JA, Aitman TJ, Cornall RJ. Genetic analysis of autoimmune type 1 diabetes mellitus in mice. Nature 1991; 351: 542-7.
    CrossrefPubMedSearch in Google Scholar