Oral insulin immunotherapy in children at risk for type 1 diabetes in a randomized trial

Background Oral administration of antigen can induce immunological tolerance. Insulin is a key autoantigen in childhood type 1 diabetes with insulin autoimmunity often appearing in the first years of life. Here, oral insulin was given as antigen-specific immunotherapy before the onset of autoimmunity in children from age 6 months to assess its safety and actions on immunity and the gut microbiome. Methods A phase I/II randomized controlled trial was performed in 44 islet autoantibody-negative children aged 6 months to 2 years with genetic risk for type 1 diabetes. Children were randomized 1:1 to daily oral insulin (7.5 mg with dose escalation to 67.5 mg) or placebo for 12 months. Primary outcome was safety and immune efficacy pre-specified as hypoglycemia and induction of antibody or T cell responses to insulin, respectively. Results Oral insulin was well tolerated with no changes in metabolic variables. Immune responses to insulin were observed in both children who received insulin (55%) and placebo (67%), and were modified by the INSULIN gene. Among children with type 1 diabetes-susceptible INSULIN genotype, antibody responses to insulin were more frequent in insulin-treated (cumulative response, 75.8%) as compared to placebo-treated children (18.2%; P =0.0085), and T cell responses to insulin were modified by treatment-independent inflammatory episodes. Changes in the microbiome were related to INSULIN genotype. Conclusion The study demonstrated that oral insulin immunotherapy in young genetically at-risk children was safe and engaged the adaptive immune system in an INSULIN genotype-dependent manner, and linked inflammatory episodes to the activation of insulin-responsive T cells. Trial registration Clinicaltrials.gov NCT02547519 Funding German Center for Diabetes Research (DZD e.V.), Juvenile Diabetes Research Foundation (JDRF, grant 1-SRA-2018-546-S-B), Federal Ministry of Education and Research (BMBF, grant FKZ01KX1818).