High-Dose Oral Insulin in Young Children at High Risk for Type 1 Diabetes: The Pre-POInT-early Clinical Trial

Oral administration of antigen can induce immunological tolerance. We studied the safety and immunological effects of daily oral insulin immunotherapy for 12 months in 44 islet autoantibody-negative children aged 6 months to 2 years with elevated risk for type 1 diabetes randomized 1:1 to insulin or placebo. Oral insulin was well tolerated with no changes in metabolic variables. The primary immune efficacy outcome was an induction of antibody or T cell responses to oral insulin. Outcome was not different between treatment groups and responses were observed in both children who received insulin (55‰) or placebo (67‰). Responses were modified by the type 1 diabetes INSULIN gene. Antibody responses to insulin were more frequent in insulin- as compared to placebo-treated children with a susceptible genotype. Oral insulin altered the gut microbiome in an INSULIN genotype-related manner. Concomitant inflammation modified the in vitro T cell responses to insulin in children with susceptible genotypes. Oral insulin immunotherapy in young genetically at-risk children may engage the adaptive immune system in an INSULIN genotype-dependent manner, potentially by changes in the microbiome.