Effects of high-dose oral insulin on immune responses in children at high risk for type 1 diabetes: the Pre-POINT randomized clinical trial

Ezio Bonifacio, Anette-G Ziegler, Georgeanna Klingensmith, Edith Schober, Polly J Bingley, Marietta Rottenkolber, Anke Theil, Anne Eugster, Ramona Puff, Claudia Peplow, Florian Buettner, Karin Lange, Jörg Hasford, Peter Achenbach, Pre-POINT Study Group

Research output: Contribution to journalArticle (Academic Journal)peer-review

150 Citations (Scopus)


IMPORTANCE: Exposing the oral mucosa to antigen may stimulate immune tolerance. It is unknown whether treatment with oral insulin can induce a tolerogenic immune response in children genetically susceptible to type 1 diabetes.

OBJECTIVE: To assess the immune responses and adverse events associated with orally administered insulin in autoantibody-negative, genetically at-risk children.

DESIGN, SETTING, AND PARTICIPANTS: The Pre-POINT study, a double-blind, placebo-controlled, dose-escalation, phase 1/2 clinical pilot study performed between 2009 and 2013 in Germany, Austria, the United States, and the United Kingdom and enrolling 25 islet autoantibody-negative children aged 2 to 7 years with a family history of type 1 diabetes and susceptible human leukocyte antigen class II genotypes. Follow-up was completed in August 2013.

INTERVENTIONS: Children were randomized to receive oral insulin (n = 15) or placebo (n = 10) once daily for 3 to 18 months. Nine children received insulin with dose escalations from 2.5 to 7.5 mg (n = 3), 2.5 to 22.5 mg (n = 3), or 7.5 to 67.5 mg (n = 3) after 6 months; 6 children only received doses of 22.5 mg (n = 3) or 67.5 mg (n = 3).

MAIN OUTCOMES AND MEASURES: An immune response to insulin, measured as serum IgG and saliva IgA binding to insulin, and CD4+ T-cell proliferative responses to insulin.

RESULTS: Increases in IgG binding to insulin, saliva IgA binding to insulin, or CD4+ T-cell proliferative responses to insulin were observed in 2 of 10 (20% [95% CI, 0.1%-45%]) placebo-treated children and in 1 of 6 (16.7% [95% CI, 0.1%-46%]) children treated with 2.5 mg of insulin, 1 of 6 (16.7%[ 95% CI, 0.1%-46%]) treated with 7.5 mg, 2 of 6 (33.3% [95% CI, 0.1%-71%]) treated with 22.5 mg, and 5 of 6 (83.3% [ 95% CI, 53%-99.9%]) treated with 67.5 mg (P = .02). Insulin-responsive T cells displayed regulatory T-cell features after oral insulin treatment. No hypoglycemia, IgE responses to insulin, autoantibodies to glutamic acid decarboxylase or insulinoma-associated antigen 2, or diabetes were observed. Adverse events were reported in 12 insulin-treated children (67 events) and 10 placebo-treated children (35 events).

CONCLUSIONS AND RELEVANCE: In this pilot study of children at high risk for type 1 diabetes, daily oral administration of 67.5 mg of insulin, compared with placebo, resulted in an immune response without hypoglycemia. These findings support the need for a phase 3 trial to determine whether oral insulin can prevent islet autoimmunity and diabetes in such children.

TRIAL REGISTRATION: isrctn.org Identifier: ISRCTN76104595.

Original languageEnglish
Pages (from-to)1541-1549
Number of pages9
JournalJAMA - Journal of the American Medical Association
Issue number15
Publication statusPublished - 21 Apr 2015


  • Administration, Oral
  • Autoantibodies
  • Autoimmunity
  • CD4-Positive T-Lymphocytes
  • Child
  • Child, Preschool
  • Diabetes Mellitus, Type 1
  • Double-Blind Method
  • Female
  • Humans
  • Hypoglycemic Agents
  • Immunoglobulin A
  • Immunoglobulin G
  • Insulin
  • Male
  • Pilot Projects


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