High-Dose Oral Insulin May Thwart Type 1 Diabetes in High-Risk Children

A high-dose oral insulin evoked an immune response to insulin without hypoglycemia in children at high risk for type 1 diabetes.

When compared with placebo, daily oral administration of high-dose insulin induced an immune response without hypoglycemia in children at high risk for type 1 diabetes, results from the Pre-POINT study indicate.

“A few precisely defined proteins are often the trigger for immune responses that cause autoimmune diseases. This has led to the experimental use of antigen-specific therapies to prevent, stabilize, or reverse immune-related diseases,” Ezio Bonifacio, PhD, of the DFG Center for Regenerative Therapies Dresden at Technische Universität Dresden in Germany, and colleagues wrote in JAMA.

They noted that researchers have achieved some success with this approach in allergies and multiple sclerosis but have yet to do so in type 1 diabetes.

In asymptomatic people, type 1 diabetes can be detected by the presence of islet autoantibodies that develop in children. According to background information in the study, antigen-specific therapy using insulin before development of these autoantibodies may help stimulate immune responses that prevent autoimmunity and the subsequent development of type 1 diabetes in children who are genetically at risk.

In animal models, oral insulin has reduced the development of diabetes. To examine whether it can also trigger a protective immune response in humans, Bonifacio and colleagues conducted the Pre-POINT study.

In the double-blind, phase 1/2 clinical pilot study, the researchers randomly assigned 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 to oral insulin at varying doses (n=15) or placebo (n=10) once daily for 3 to 18 months.

They assessed immune response to insulin by measuring serum immunoglobulin G (IgG) and saliva immunoglobulin A (IgA) binding to insulin as well as CD4+ T-cell proliferative responses to insulin.

After 6 months, nine children received insulin with dose escalations from 2.5 mg to 7.5 mg (n=3), 2.5 to 22.5 mg (n=3) or 7.5 to 67.5 mg (n=3), while six children received doses of 22.5 mg (n=3) or 67.5 mg (n=3) only.

Immune responses were observed in the following:

  • Two of 10 children who received placebo (20%);
  • One of six children treated with 2.5 mg of insulin (16.7%);
  • One of six children treated with 7.5 mg of insulin (16.7%);
  • Two of six children treated with 22.5 mg of insulin (33.3%); and
  • Five of six children treated with 67.5 mg of insulin (83.3%; P=.02).

In addition, the researchers reported that insulin-responsive T cells displayed regulatory T-cell features after treatment with oral insulin.

They also found no hypoglycemia, immunoglobulin E (IgE) responses to insulin, autoantibodies to gluatmic acid decarboxylase or insulinoma-associated antigen 2, or diabetes, according to the data.

Sixty-seven adverse events were reported in 12 children treated with insulin and 35 in 10 children who received placebo. Incidence and type of adverse events did not appear to differ between study groups.

“The Pre-POINT pilot study demonstrated that daily oral administration of 67.5 mg of insulin to genetically at-risk healthy children without signs of islet autoimmunity resulted in an immune response without hypoglycemia. The immune response observed in insulin-treated children did not display the features typically associated with type 1 diabetes,” the researchers wrote.

They concluded that their findings support a phase 3 trial to determine whether oral insulin can prevent autoantibodies or type 1 diabetes in these children.

In an accompanying editorial, Jay S. Skyler, MD, of the University of Miami Miller School of Medicine, discussed the results.

“It is now possible to identify children at increased risk for type 1 diabetes at birth, and there is an identifiable sequence of events that culminates in impaired insulin secretion and overt type 1 diabetes,” Skyler wrote.

“What is missing are interventions to arrest this process prior to irreversible damage to the pancreatic beta cell. The promise of autoantigen-specific therapy for prevention of type 1 diabetes in humans has yet to be realized. The Pre-POINT study provides additional evidence to inform trial design and increases enthusiasm for cautiously moving forward with a study of primary prevention in genetically screened children.”


  1. Bonifacio E et al. JAMA. 2015;313(15):1541-1549.
  2. Skyler JS. JAMA. 2015;313(15):1520-1521.