Effects of High-Dose Oral Insulin on Immune Responses in Children at High Risk for Type 1 Diabetes: The Pre-POINT Randomized Clinical Trial | Pediatrics | JAMA | JAMA Network
[Skip to Navigation]
Access to paid content on this site is currently suspended due to excessive activity being detected from your IP address Please contact the publisher to request reinstatement.
Ziegler  AG, Nepom  GT.  Prediction and pathogenesis in type 1 diabetes.  Immunity. 2010;32(4):468-478.PubMedGoogle ScholarCrossref
Trentham  DE, Dynesius-Trentham  RA, Orav  EJ,  et al.  Effects of oral administration of type II collagen on rheumatoid arthritis.  Science. 1993;261(5129):1727-1730.PubMedGoogle ScholarCrossref
Takiishi  T, Korf  H, Van Belle  TL,  et al.  Reversal of autoimmune diabetes by restoration of antigen-specific tolerance using genetically modified Lactococcus lactis in mice.  J Clin Invest. 2012;122(5):1717-1725.PubMedGoogle ScholarCrossref
Stern  JN, Keskin  DB, Kato  Z,  et al.  Promoting tolerance to proteolipid protein-induced experimental autoimmune encephalomyelitis through targeting dendritic cells.  Proc Natl Acad Sci U S A. 2010;107(40):17280-17285.PubMedGoogle ScholarCrossref
Anagnostou  K, Islam  S, King  Y,  et al.  Assessing the efficacy of oral immunotherapy for the desensitisation of peanut allergy in children (STOP II): a phase 2 randomised controlled trial.  Lancet. 2014;383(9925):1297-1304.PubMedGoogle ScholarCrossref
Lutterotti  A, Yousef  S, Sputtek  A,  et al.  Antigen-specific tolerance by autologous myelin peptide-coupled cells: a phase 1 trial in multiple sclerosis.  Sci Transl Med. 2013;5(188):188ra75.PubMedGoogle ScholarCrossref
Näntö-Salonen  K, Kupila  A, Simell  S,  et al.  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. 2008;372(9651):1746-1755.PubMedGoogle ScholarCrossref
Diabetes Prevention Trial—Type 1 Diabetes Study Group.  Effects of insulin in relatives of patients with type 1 diabetes mellitus.  N Engl J Med. 2002;346(22):1685-1691.PubMedGoogle ScholarCrossref
Skyler  JS, Krischer  JP, Wolfsdorf  J,  et al.  Effects of oral insulin in relatives of patients with type 1 diabetes: the Diabetes Prevention Trial—Type 1.  Diabetes Care. 2005;28(5):1068-1076.PubMedGoogle ScholarCrossref
Ziegler  AG, Rewers  M, Simell  O,  et al.  Seroconversion to multiple islet autoantibodies and risk of progression to diabetes in children.  JAMA. 2013;309(23):2473-2479.PubMedGoogle ScholarCrossref
Ziegler  AG, Bonifacio  E; BABYDIAB-BABYDIET Study Group.  Age-related islet autoantibody incidence in offspring of patients with type 1 diabetes.  Diabetologia. 2012;55(7):1937-1943.PubMedGoogle ScholarCrossref
Arif  S, Tree  TI, Astill  TP,  et al.  Autoreactive T cell responses show proinflammatory polarization in diabetes but a regulatory phenotype in health.  J Clin Invest. 2004;113(3):451-463.PubMedGoogle ScholarCrossref
Unger  WW, Velthuis  J, Abreu  JR,  et al.  Discovery of low-affinity preproinsulin epitopes and detection of autoreactive CD8 T-cells using combinatorial MHC multimers.  J Autoimmun. 2011;37(3):151-159.PubMedGoogle ScholarCrossref
Zhang  ZJ, Davidson  L, Eisenbarth  G, Weiner  HL.  Suppression of diabetes in nonobese diabetic mice by oral administration of porcine insulin.  Proc Natl Acad Sci U S A. 1991;88(22):10252-10256.PubMedGoogle ScholarCrossref
Bresson  D, Togher  L, Rodrigo  E,  et al.  Anti-CD3 and nasal proinsulin combination therapy enhances remission from recent-onset autoimmune diabetes by inducing Tregs.  J Clin Invest. 2006;116(5):1371-1381.PubMedGoogle ScholarCrossref
Bonifacio  E, Hummel  M, Walter  M, Schmid  S, Ziegler  AG.  IDDM1 and multiple family history of type 1 diabetes combine to identify neonates at high risk for type 1 diabetes.  Diabetes Care. 2004;27(11):2695-2700.PubMedGoogle ScholarCrossref
Aly  TA, Ide  A, Jahromi  MM,  et al.  Extreme genetic risk for type 1A diabetes.  Proc Natl Acad Sci U S A. 2006;103(38):14074-14079.PubMedGoogle ScholarCrossref
Koczwara  K, Muller  D, Achenbach  P, Ziegler  AG, Bonifacio  E.  Identification of insulin autoantibodies of IgA isotype that preferentially target non-human insulin.  Clin Immunol. 2007;124(1):77-82.PubMedGoogle ScholarCrossref
Williams  AJ, Bingley  PJ, Bonifacio  E, Palmer  JP, Gale  EA.  A novel micro-assay for insulin autoantibodies.  J Autoimmun. 1997;10(5):473-478.PubMedGoogle ScholarCrossref
Eugster  A, Lindner  A, Heninger  AK,  et al.  Measuring T cell receptor and T cell gene expression diversity in antigen-responsive human CD4+ T cells.  J Immunol Methods. 2013;400-401:13-22.PubMedGoogle ScholarCrossref
Bonifacio  E, Scirpoli  M, Kredel  K, Füchtenbusch  M, Ziegler  AG.  Early autoantibody responses in prediabetes are IgG1 dominated and suggest antigen-specific regulation.  J Immunol. 1999;163(1):525-532.PubMedGoogle Scholar
Bonifacio  E, Yu  L, Williams  AK,  et al.  Harmonization of glutamic acid decarboxylase and islet antigen-2 autoantibody assays for national institute of diabetes and digestive and kidney diseases consortia.  J Clin Endocrinol Metab. 2010;95(7):3360-3367.PubMedGoogle ScholarCrossref
Miyara  M, Gorochov  G, Ehrenstein  M, Musset  L, Sakaguchi  S, Amoura  Z.  Human FoxP3+ regulatory T cells in systemic autoimmune diseases.  Autoimmun Rev. 2011;10(12):744-755.PubMedGoogle ScholarCrossref
Hummel  S, Pflüger  M, Hummel  M, Bonifacio  E, Ziegler  AG.  Primary dietary intervention study to reduce the risk of islet autoimmunity in children at increased risk for type 1 diabetes: the BABYDIET study.  Diabetes Care. 2011;34(6):1301-1305.PubMedGoogle ScholarCrossref
Fonte  P, Araújo  F, Reis  S, Sarmento  B.  Oral insulin delivery: how far are we?  J Diabetes Sci Technol. 2013;7(2):520-531.PubMedGoogle ScholarCrossref
Svingos  RS, Fernandez  EM, Reeder  DN, Parker  JJ.  Life-threatening hypoglycemia associated with intentional insulin ingestion.  Pharmacotherapy. 2013;33(3):e28-e33.PubMedGoogle ScholarCrossref
Barker  JM, McFann  KK, Orban  T.  Effect of oral insulin on insulin autoantibody levels in the Diabetes Prevention Trial Type 1 oral insulin study.  Diabetologia. 2007;50(8):1603-1606.PubMedGoogle ScholarCrossref
Achenbach  P, Koczwara  K, Knopff  A, Naserke  H, Ziegler  AG, Bonifacio  E.  Mature high-affinity immune responses to (pro)insulin anticipate the autoimmune cascade that leads to type 1 diabetes.  J Clin Invest. 2004;114(4):589-597.PubMedGoogle ScholarCrossref
Syed  A, Garcia  MA, Lyu  SC,  et al.  Peanut oral immunotherapy results in increased antigen-induced regulatory T-cell function and hypomethylation of forkhead box protein 3 (FOXP3).  J Allergy Clin Immunol. 2014;133(2):500-510.PubMedGoogle ScholarCrossref
Vinuesa  CG, Linterman  MA, Goodnow  CC, Randall  KL.  T cells and follicular dendritic cells in germinal center B-cell formation and selection.  Immunol Rev. 2010;237(1):72-89.PubMedGoogle ScholarCrossref
Preliminary Communication
April 21, 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

Author Affiliations
  • 1DFG Center for Regenerative Therapies Dresden, Faculty of Medicine, Technische Universität Dresden, Dresden, Germany
  • 2Paul Langerhans Institute Dresden, German Center for Diabetes Research (DZD), Technische Universität Dresden, Dresden, Germany
  • 3Forschergruppe Diabetes e.V., Neuherberg, Germany
  • 4Institute of Diabetes Research, Helmholtz Zentrum München, and Forschergruppe Diabetes, Klinikum rechts der Isar, Technische Universität München, Munich, Germany
  • 5Barbara Davis Center for Childhood Diabetes, University of Colorado School of Medicine, Aurora
  • 6Department of Pediatrics, Medical University of Vienna, Vienna, Austria
  • 7School of Clinical Sciences, University of Bristol, Bristol, United Kingdom
  • 8Institute for Medical Information Sciences, Biometry, and Epidemiology, Ludwig-Maximilians-Universitaet, Munich, Germany
  • 9Institute of Computational Biology, Helmholtz Zentrum München
  • 10Department of Medical Psychology, Hannover Medical School, Hannover, Germany
JAMA. 2015;313(15):1541-1549. doi:10.1001/jama.2015.2928

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