Typ-1-Diabetes im asymptomatischen Frühstadium

Orales Insulin zur präventiven Behandlung
Leitthema
  • 12 Downloads

Zusammenfassung

Hintergrund

Insulin ist bei Kindern, die Typ-1-Diabetes entwickeln, meist das erste Ziel der Autoimmunreaktion und gilt deshalb als aussichtsreicher Kandidat für eine antigenspezifische Immunmodulation zur präventiven Behandlung der Erkrankung.

Studienresultate

Weltweit wurden in klinischen Studien schon mehrere hundert Kinder mit oralem Insulin in verschiedenen Dosierungen behandelt, ohne dass Nebenwirkungen auftraten. In 2 großen Studien konnte insgesamt kein präventiver Effekt mit täglich 7,5 mg Insulin oral bei betazellautoantikörperpositiven Personen erzielt werden, obgleich eine verzögerte Diabetesentwicklung in Subgruppen beobachtet wurde. In einer Pilotstudie jedoch wurde mit täglich 67,5 mg Insulin oral eine regulatorische Immunantwort gegen Insulin induziert.

Laufende Studien mit hochdosiertem oralem Insulin

Der präventive Effekt von täglich 67,5 mg Insulin oral auf die Diabetesentwicklung wird gegenwärtig geprüft; bei betazellautoantikörperpositiven Kindern mit einem asymptomatischen Frühstadium des Typ-1-Diabetes (Fr1da-Insulin-Interventions-Studie) sowie bei autoantikörpernegativen Kindern mit genetischem Risiko für Typ-1-Diabetes (POInT [„primary oral insulin trial“]).

Schlüsselwörter

Autoimmundiabetes Immunmodulation Prävention und Kontrolle Autoantigene Kind 

Asymptomatic early stage type 1 diabetes

Oral insulin as a preventive treatment

Abstract

Background

Insulin is usually the first target of the autoimmune response in children developing type 1 diabetes and is therefore considered a promising candidate for an antigen-specific immunomodulation for the preventive treatment of the disease.

Study results

To date, several hundred of children worldwide have been treated with oral insulin in clinical studies, in various doses and without adverse reactions. Two large studies could not achieve a preventive effect with 7.5 mg oral insulin daily in β‑cell autoantibody-positive individuals overall, although delayed diabetes development was observed in subgroups. In a pilot study, 67.5 mg oral insulin daily induced a regulatory immune response against insulin.

Ongoing studies with high-dose oral insulin

The preventive effect of 67.5 mg oral insulin daily on diabetes development is currently under investigation: in β‑cell-autoantibody-positive children with an asymptomatic early stage of type 1 diabetes (Fr1da-Insulin-Intervention study) and in autoantibody-negative children with genetic risk for type 1 diabetes (POInT study [POInT: Primary Oral Insulin Trial]).

Keywords

Autoimmune diabetes Immunomodulation Prevention & control Autoantigens Child 

Notes

Einhaltung ethischer Richtlinien

Interessenkonflikt

P. Achenbach gibt an, dass kein Interessenkonflikt besteht.

Dieser Beitrag beinhaltet keine vom Autor durchgeführten Studien an Menschen oder Tieren.

Literatur

  1. 1.
    Achenbach P, Bonifacio E, Koczwara K, Ziegler AG (2005) Natural history of type 1 diabetes. Diabetes 54(Suppl 2):S25–S31CrossRefPubMedGoogle Scholar
  2. 2.
    Nakayama M, Abiru N, Moriyama H et al (2005) Prime role for an insulin epitope in the development of type 1 diabetes in NOD mice. Nature 435:220–223CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Ziegler AG, Hummel M, Schenker M, Bonifacio E (1999) 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 48:460–468CrossRefPubMedGoogle Scholar
  4. 4.
    Kimpimaki T, Kulmala P, Savola K et al (2002) Natural history of beta-cell autoimmunity in young children with increased genetic susceptibility to type 1 diabetes recruited from the general population. J Clin Endocrinol Metab 87:4572–4579CrossRefPubMedGoogle Scholar
  5. 5.
    Yu L, Robles DT, Abiru N et al (2000) Early expression of antiinsulin autoantibodies of humans and the NOD mouse: evidence for early determination of subsequent diabetes. Proc Natl Acad Sci USA 97:1701–1706CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Ziegler AG, Bonifacio E, Group B (2012) Age-related islet autoantibody incidence in offspring of patients with type 1 diabetes. Diabetologia 55:1937–1943CrossRefPubMedGoogle Scholar
  7. 7.
    Parikka V, Nanto-Salonen K, Saarinen M et al (2012) Early seroconversion and rapidly increasing autoantibody concentrations predict prepubertal manifestation of type 1 diabetes in children at genetic risk. Diabetologia 55:1926–1936CrossRefPubMedGoogle Scholar
  8. 8.
    Krischer JP, Lynch KF, Schatz DA et al (2015) The 6 year incidence of diabetes-associated autoantibodies in genetically at-risk children: the TEDDY study. Diabetologia 58:980–987CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Vardi P, Ziegler AG, Mathews JH et al (1988) Concentration of insulin autoantibodies at onset of type I diabetes. Inverse log-linear correlation with age. Diabetes Care 11:736–739CrossRefPubMedGoogle Scholar
  10. 10.
    Kent SC, Chen Y, Bregoli L et al (2005) Expanded T cells from pancreatic lymph nodes of type 1 diabetic subjects recognize an insulin epitope. Nature 435:224–228CrossRefPubMedGoogle Scholar
  11. 11.
    Achenbach P, Koczwara K, Knopff A, Naserke H, Ziegler AG, Bonifacio E (2004) Mature high-affinity immune responses to (pro)insulin anticipate the autoimmune cascade that leads to type 1 diabetes. J Clin Invest 114:589–597CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Colman PG, Steele C, Couper JJ et al (2000) Islet autoimmunity in infants with a Type I diabetic relative is common but is frequently restricted to one autoantibody. Diabetologia 43:203–209CrossRefPubMedGoogle Scholar
  13. 13.
    Kimpimaki T, Kupila A, Hamalainen AM et al (2001) 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 86:4782–4788PubMedGoogle Scholar
  14. 14.
    Barker JM, Barriga KJ, Yu L et al (2004) Prediction of autoantibody positivity and progression to type 1 diabetes: Diabetes Autoimmunity Study in the Young (DAISY). J Clin Endocrinol Metab 89:3896–3902CrossRefPubMedGoogle Scholar
  15. 15.
    Achenbach P, Lampasona V, Landherr U et al (2009) Autoantibodies to zinc transporter 8 and SLC30A8 genotype stratify type 1 diabetes risk. Diabetologia 52:1881–1888CrossRefPubMedGoogle Scholar
  16. 16.
    Ziegler AG, Rewers M, Simell O et al (2013) Seroconversion to multiple islet autoantibodies and risk of progression to diabetes in children. JAMA 309:2473–2479CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Insel RA, Dunne JL, Atkinson MA et al (2015) Staging presymptomatic type 1 diabetes: a scientific statement of JDRF, the Endocrine Society, and the American Diabetes Association. Diabetes Care 38:1964–1974CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Harrison LC, Hafler DA (2000) Antigen-specific therapy for autoimmune disease. Curr Opin Immunol 12:704–711CrossRefPubMedGoogle Scholar
  19. 19.
    Weiner HL (1997) Oral tolerance: immune mechanisms and treatment of autoimmune diseases. Immunol Today 18:335–343CrossRefPubMedGoogle Scholar
  20. 20.
    Mayer L, Shao L (2004) Therapeutic potential of oral tolerance. Nat Rev Immunol 4:407–419CrossRefPubMedGoogle Scholar
  21. 21.
    Faria AM, Weiner HL (2005) Oral tolerance. Immunol Rev 206:232–259CrossRefPubMedGoogle Scholar
  22. 22.
    Du Toit G, Roberts G, Sayre PH et al (2015) Randomized trial of peanut consumption in infants at risk for peanut allergy. N Engl J Med 372:803–813CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Gottlieb PA, Eisenbarth GS (2002) Insulin-specific tolerance in diabetes. Clin Immunol 102:2–11CrossRefPubMedGoogle Scholar
  24. 24.
    Zhang ZJ, Davidson L, Eisenbarth G, Weiner HL (1991) Suppression of diabetes in nonobese diabetic mice by oral administration of porcine insulin. Proc Natl Acad Sci USA 88:10252–10256CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Bergerot I, Fabien N, Maguer V, Thivolet C (1994) Oral administration of human insulin to NOD mice generates CD4+ T cells that suppress adoptive transfer of diabetes. J Autoimmun 7:655–663CrossRefPubMedGoogle Scholar
  26. 26.
    Harrison LC, Dempsey-Collier M, Kramer DR, Takahashi K (1996) Aerosol insulin induces regulatory CD8 gamma delta T cells that prevent murine insulin-dependent diabetes. J Exp Med 184:2167–2174CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Pham MN, Gibson C, Ryden AK et al (2016) Oral insulin (human, murine, or porcine) does not prevent diabetes in the non-obese diabetic mouse. Clin Immunol 164:28–33CrossRefPubMedGoogle Scholar
  28. 28.
    Chaillous L, Lefevre H, Thivolet C et al (2000) Oral insulin administration and residual beta-cell function in recent-onset type 1 diabetes: a multicentre randomised controlled trial. Diabete Insuline Orale group. Lancet 356:545–549CrossRefPubMedGoogle Scholar
  29. 29.
    Pozzilli P, Pitocco D, Visalli N et al (2000) No effect of oral insulin on residual beta-cell function in recent-onset type I diabetes (the IMDIAB VII). IMDIAB Group. Diabetologia 43:1000–1004CrossRefPubMedGoogle Scholar
  30. 30.
    Ergun-Longmire B, Marker J, Zeidler A et al (2004) Oral insulin therapy to prevent progression of immune-mediated (type 1) diabetes. Ann N Y Acad Sci 1029:260–277CrossRefPubMedGoogle Scholar
  31. 31.
    Skyler JS, Krischer JP, Wolfsdorf J et al (2005) Effects of oral insulin in relatives of patients with type 1 diabetes: the diabetes prevention trial—type 1. Diabetes Care 28:1068–1076CrossRefPubMedGoogle Scholar
  32. 32.
    Bonifacio E, Ziegler AG, Klingensmith G et al (2015) Effects of high-dose oral insulin on immune responses in children at high risk for type 1 diabetes: the Pre-POINT randomized clinical trial. JAMA 313:1541–1549CrossRefPubMedGoogle Scholar
  33. 33.
    Writing Committee for the Type 1 Diabetes TrialNet Oral Insulin Study G, Krischer JP, Schatz DA, Bundy B, Skyler JS, Greenbaum CJ (2017) Effect of Oral Insulin on Prevention of Diabetes in Relatives of Patients With Type 1 Diabetes: A Randomized Clinical Trial. JAMA 318:1891–1902CrossRefGoogle Scholar
  34. 34.
    Kupila A, Sipila J, Keskinen P et al (2003) Intranasally administered insulin intended for prevention of type 1 diabetes—a safety study in healthy adults. Diabetes Metab Res Rev 19:415–420CrossRefPubMedGoogle Scholar
  35. 35.
    Harrison LC, Honeyman MC, Steele CE et al (2004) Pancreatic beta-cell function and immune responses to insulin after administration of intranasal insulin to humans at risk for type 1 diabetes. Diabetes Care 27:2348–2355CrossRefPubMedGoogle Scholar
  36. 36.
    Nanto-Salonen K, Kupila A, Simell S et al (2008) Nasal insulin to prevent type 1 diabetes in children with HLA genotypes and autoantibodies conferring increased risk of disease: a double-blind, randomised controlled trial. Lancet 372:1746–1755CrossRefPubMedGoogle Scholar
  37. 37.
    Vehik K, Cuthbertson D, Ruhlig H et al (2011) Long-term outcome of individuals treated with oral insulin: diabetes prevention trial-type 1 (DPT-1) oral insulin trial. Diabetes Care 34:1585–1590CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Ziegler AG et al (2018) Früherkennung und Primärprävention des Typ-1-Diabetes. Diabetologe.  https://doi.org/10.1007/s11428-018-0337-8 Google Scholar
  39. 39.
    Raab J, Haupt F, Scholz M et al (2016) Capillary blood islet autoantibody screening for identifying pre-type 1 diabetes in the general population: design and initial results of the Fr1da study. BMJ Open 6:e11144CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Winkler C et al (2018) Früherkennung des Typ-1-Diabetes in der Fr1da-Studie. Diabetologe.  https://doi.org/10.1007/s11428-018-0336-9 Google Scholar
  41. 41.
    Böttcher I (2018) Vermeidung erkrankungsspezifischer Komplikationen bei Kindern. Diabetologe.  https://doi.org/10.1007/s11428-018-0345-8 Google Scholar

Copyright information

© Springer Medizin Verlag GmbH, ein Teil von Springer Nature 2018

Authors and Affiliations

  1. 1.Institut für DiabetesforschungHelmholtz Zentrum MünchenMünchenDeutschland

Personalised recommendations