In the JournalsPerspective

High-dose oral insulin may prevent type 1 diabetes in high-risk children

Daily high-dose oral insulin compared with placebo resulted in an immune response to insulin without hypoglycemia among children at high risk for type 1 diabetes, according to study findings published in JAMA.

“Antigen-specific therapy with insulin before the development of autoantibodies may induce protective immune responses that prevent the emergence of autoimmunity and type 1 diabetes in genetically at-risk children,” the researchers wrote. “Therefore, we assessed whether oral insulin in children without prior overt autoimmunity can induce a potentially protective immune response to an autoantigen without causing adverse effects.”

Ezio Bonifacio, PhD, of the DFG Center for Regenerative Therapies in Dresden, Germany, and colleagues evaluated 25 islet autoantibody-negative children aged 2 to 7 years from the Pre-POINT study to determine the immune responses and adverse events association with orally administered insulin. Participants had a family history of type 1 diabetes and were susceptible to human leukocyte antigen class II genotypes.

Participants were randomly assigned to oral insulin (n = 15) or placebo (n = 10) once daily for 3 to 18 months. Dose escalations from 2.5 mg to 7.5 mg (n = 3), 2.5 mg to 22.5 mg (n = 3) or 7.5 mg to 67.5 mg (n = 3) were administered to nine participants after 6 months and six participants received only 22.5 mg (n = 3) or 67.5 mg (n = 3).

Study researcher Anette-Gabriele Ziegler, MD, from the Institut für Diabetesforschung in Germany, said in a press release that the unique aspect of the study is that the insulin was administered as a prophylactic before the participants developed an autoimmune response.

“This is a revolutionary way to prevent type 1 diabetes, but it is quite logical that if the body’s immune system doesn’t learn how to make the protective responses by itself, we need to give it a little help,” Ziegler said.

Sixty percent of participants in the insulin group and 20% in the placebo group had antibody or T-cell responses (P = .02 for trend).

Immune responses to insulin also were revealed for one participant treated with 2.5 mg, one participant treated with 7.5 mg, two treated with 22.5 mg, five treated with 67.5 mg and one treated with placebo (P = .051).

“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, results in an immune response without hypoglycemia,” the researchers wrote. “These findings support the need for a phase 3 trial to determine whether oral insulin can prevent islet autoimmunity and diabetes in such children.”

In an accompanying editorial, Jay S. Skyler, MD, of the University of Miami Miller School of Medicine, wrote that the identification of children at increased risk for type 1 diabetes at birth is now possible.

“What is missing are interventions to arrest this process prior to irreversible damage to the pancreatic beta cell,” he wrote. “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.” – by Amber Cox

Disclosure: The researchers report no relevant financial disclosures.

Daily high-dose oral insulin compared with placebo resulted in an immune response to insulin without hypoglycemia among children at high risk for type 1 diabetes, according to study findings published in JAMA.

“Antigen-specific therapy with insulin before the development of autoantibodies may induce protective immune responses that prevent the emergence of autoimmunity and type 1 diabetes in genetically at-risk children,” the researchers wrote. “Therefore, we assessed whether oral insulin in children without prior overt autoimmunity can induce a potentially protective immune response to an autoantigen without causing adverse effects.”

Ezio Bonifacio, PhD, of the DFG Center for Regenerative Therapies in Dresden, Germany, and colleagues evaluated 25 islet autoantibody-negative children aged 2 to 7 years from the Pre-POINT study to determine the immune responses and adverse events association with orally administered insulin. Participants had a family history of type 1 diabetes and were susceptible to human leukocyte antigen class II genotypes.

Participants were randomly assigned to oral insulin (n = 15) or placebo (n = 10) once daily for 3 to 18 months. Dose escalations from 2.5 mg to 7.5 mg (n = 3), 2.5 mg to 22.5 mg (n = 3) or 7.5 mg to 67.5 mg (n = 3) were administered to nine participants after 6 months and six participants received only 22.5 mg (n = 3) or 67.5 mg (n = 3).

Study researcher Anette-Gabriele Ziegler, MD, from the Institut für Diabetesforschung in Germany, said in a press release that the unique aspect of the study is that the insulin was administered as a prophylactic before the participants developed an autoimmune response.

“This is a revolutionary way to prevent type 1 diabetes, but it is quite logical that if the body’s immune system doesn’t learn how to make the protective responses by itself, we need to give it a little help,” Ziegler said.

Sixty percent of participants in the insulin group and 20% in the placebo group had antibody or T-cell responses (P = .02 for trend).

Immune responses to insulin also were revealed for one participant treated with 2.5 mg, one participant treated with 7.5 mg, two treated with 22.5 mg, five treated with 67.5 mg and one treated with placebo (P = .051).

“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, results in an immune response without hypoglycemia,” the researchers wrote. “These findings support the need for a phase 3 trial to determine whether oral insulin can prevent islet autoimmunity and diabetes in such children.”

In an accompanying editorial, Jay S. Skyler, MD, of the University of Miami Miller School of Medicine, wrote that the identification of children at increased risk for type 1 diabetes at birth is now possible.

“What is missing are interventions to arrest this process prior to irreversible damage to the pancreatic beta cell,” he wrote. “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.” – by Amber Cox

Disclosure: The researchers report no relevant financial disclosures.

    Perspective
    Michael Haller

    Michael Haller

    Following the post-hoc observation from the diabetes prevention trial type 1 that oral insulin given to subjects with high titer oral insulin autoantibodies resulted in a 4.5- to 5-year delay in the onset of type 1 diabetes, the concept of using oral insulin at higher doses and in subjects who have not yet developed serological evidence of autoimmunity has been of great interest.

    The Pre-POINT study represents an important effort to further move, from concept to reality, the idea of antigen-based primary prevention therapy in children at risk for type 1 diabetes. In summary, this effort showed that oral insulin given at up to 67.5 mg daily was safe and induced immune responses that could be consistent with promoting tolerance (as opposed to  immune responses consistent with autoimmunity). While these data are preliminary in terms of potential application to a definitive therapy to prevent type 1 diabetes, they nevertheless represent an important step forward in demonstrating proof of concept for a safe and economically feasible therapy that could be applied to a large population of at-risk children.

    In this study, the children who were randomized to receive oral insulin or placebo were at the highest genetic risk measurable for developing type 1 diabetes. As such, the data may not (as the authors openly discuss) be representative of responses that would be seen in all children. Given that the children tested represent less than 1% of the children who will ultimately develop diabetes, additional studies will clearly be needed to determine if immune responses in children with less genetic risk for type 1 diabetes are similar.  In addition, given that the immunological studies performed in this analysis have yet to be fully validated or considered standard procedure, it is difficult to be definitive when trying to classify the type of immune response observed in the subjects.

    The next steps for this approach will, as the authors note, be studies designed to determine optimal dosing for generating a tolerogenic immune response to insulin while following children long enough to determine if this approach indeed holds the capacity to prevent the development of diabetes-related autoantibodies and ultimately type 1 diabetes. If these efforts prove efficacious, and if additional efforts demonstrate the capacity for this approach to provide benefit in children of other genetic risk categories, it may indeed provide an economically feasible rationale for performing widespread newborn genetic screening for type 1 diabetes risk. Nevertheless, these studies will take several years to complete, and as such, we will have to wait for additional data to be generated before determining if this approach will have a major impact on realizing the dream of preventing type 1 diabetes.

    • Michael Haller, MD, MS-CI
    • Associate Professor and Fellowship Director
      Pediatric Endocrinology
      University of Florida

    Disclosures: Haller reports no relevant financial disclosures.