Oral Insulin May Thwart Type 1 Diabetes in High-Risk Kids

Marlene Busko

April 21, 2015

In the Pre-POINT pilot study, five of six children who were at extremely high risk of developing type 1 diabetes and who received a high dose of oral insulin had a protective immune response, and the insulin did not cause 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" and offer a glimmer of hope for the development of a vaccine against type 1 diabetes, the researchers speculate.

The study is published in the April 21, 2015 issue of the Journal of the American Medical Association.

Lead author Ezio Bonifacio, PhD, from the DFG Center of Regenerative Therapies in Dresden, Germany, explained the aim of the study to Medscape Medical News: "We are trying to stop the actual seroconversion…[which is the start of the process of developing type 1 diabetes and which occurs when] a child becomes positive for antibodies against the insulin-producing cells of the pancreas.

"We believe that by exposing the immune system to insulin very early and by mouth we are strengthening the controlling type of immunity, and fewer children will actually start the disease process," he said. If subsequent research is favorable, it is possible that, 10 years from now, there could be a vaccine to prevent type 1 diabetes developing in high-risk infants, according to Dr Bonifacio.

Writing in an accompanying editorial, Jay S Skyler, MD, from the Diabetes Research Institute, University of Miami Miller School of Medicine, Florida, is "cautiously optimistic" that these findings could lead to primary prevention of type 1 diabetes.

"The promise of autoantigen-specific therapy for prevention of type 1 diabetes in humans has yet to be realized," he observes. However, "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."

And Julia Greenstein, vice president of discovery research at the Juvenile Diabetes Research Fund (JDRF), which helped to fund the research, said: "JDRF is very encouraged by the results of the Pre-POINT study as a first step to potentially prevent type 1 diabetes in children who are at high risk for getting it.

"This is a significant finding.…These study results are exciting and bring us one step closer to the potential of seeing an oral vaccination strategy to prevent type 1 diabetes," she commented in a JDRF statement.

What Dose of Oral Insulin Is Best?

Dr Bonifacio and colleagues conducted their placebo-controlled, dose-escalation, phase 1–2 pilot study of oral insulin in children who were at extremely high risk of developing type 1 diabetes but had no diabetes autoantibodies. From September 2009 to April 2013, they assessed 369 children for eligibility at four outpatient sites in Germany, Austria, the United States, and the United Kingdom.

To be eligible, children had to be 2 to 7 years old and seronegative for autoantibodies to insulin, glutamic acid decarboxylase 65 (GAD65), and insulinoma-associated antigen 2 (IA-2). They also had to have two first-degree relatives or a sibling with type 1 diabetes and have certain HLA haplotypes.

The researchers randomized 25 children, 10 boys and 15 girls, who had a mean age of 5.1 years.

Fifteen children received the following doses of oral insulin:

  • 2.5 mg/day for 6 months, then 7.5 mg/day for 3 to 12 months (n=3).

  • 2.5 mg/day for 6 months, then 22.5 mg/day for 3 to 12 months (n=3).

  • 7.5 mg/day for 6 months, then 67.5 mg/day for 3 to 12 months (n=3).

  • 22.5 mg/day for 3 to 12 months (n=3).

  • 67.5 mg/day for 3 to 12 months (n=3).

Ten children received placebo for 2.5 to 20.5 months. Parents were instructed to sprinkle the placebo or the oral insulin on food that contained glucose.

The primary outcome was a positive immune response to insulin, defined as an increase in IgG binding to insulin or saliva IgA binding to insulin or a CD4+ T-cell proliferative response to insulin.

Percentage of Children With a Positive Immune Response to Insulin*

Placebo or Insulin (mg) Number/Total Children (%) 95% CI
Placebo 2/10 (20) 0.1–45
2.5 1/6 (17) 0.1–46
7.5 1/6 (17) 0.1–46
22.5 2/6 (33) 0.1–71
67.5 5/6 (83) 53–99.9
*An increase in serum IgG binding to insulin or saliva IgA binding to insulin or a CD4+ T-cell proliferative response to insulin

Six children (including three of six children ultimately treated with 67.5 mg insulin and one of 10 children treated with placebo) had increased serum IgG binding to insulin. One child who received 22.5-mg insulin had strong saliva IgA binding to insulin. Four children who received insulin and one child who received placebo had a positive T-cell response.

The highest dose of insulin was much greater than that used in previous trials, Dr Skyler notes in his editorial, adding, "It is clear from previous studies that the dose of insulin is critically important, and this study informs future research efforts."

None of the children developed hypoglycemia. There were 67 adverse events in 15 insulin-treated children vs 35 events in 10 children in the placebo group ( P > .90), most often infections. There was no evidence of allergy to insulin.

"We had to use relatively large amounts of insulin, and we were pleased to see that there were no unwanted side effects and thus far only signs that mimic what normally happens in children who don't get type 1 diabetes," said Dr Bonifacio.

"This is the first time we are seeing any sort of response by the immune system to orally administered insulin in children," he added.

"Many people thought that the treatment would fail because the insulin would be broken up by the time it gets through the stomach. However, we believe that most of the response is happening while insulin is still in the mouth. The same seems to be true in some recent studies when increasing doses of protein were given to children with peanut allergy."

For this reason, he and his team recommend that "future studies administer insulin with glucose-containing foods," as was done in PrePOINT.

However, while the results are "encouraging," this was a small sample of children and a short study duration, they acknowledge.

Moreover, children with this type of genetic profile account for less than 1% of children who ultimately develop type 1 diabetes, so oral insulin might have a different effect in children with a lower genetic risk.

A Type 1 Diabetes Vaccine in 10 Years?

"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," Dr Skyler writes.

"What is missing are interventions to arrest this process prior to irreversible damage to the pancreatic beta cells."

However, researchers are investigating several very different ways to prevent type 1 diabetes from developing — including the use of a cocktail of peptides from proinsulin or of methyldopa, he notes.

The current study will generate interest in other approaches, such as those using lower doses of oral insulin or intranasal insulin to prevent beta-cell destruction in children who already have autoantibodies, Dr Bonifacio said.

If any of these strategies are successful, which should become apparent in a few years, "then we could have something that works in children who have started the [seroconversion] process within the next 5 years," he speculated.

Meanwhile, his group is beginning another project to validate their pilot study in high-risk children who are 6 months to 2 years old— which they now know is the optimum age for peak incidence of islet autoantibodies.

"If we get similar effects in this follow-up study, which we hope will be finished in 2017, we will move to a much larger clinical study, where we will test whether the treatment reduces the number of children who become islet-autoantibody positive and the number of children who [subsequently] develop type 1 diabetes," he explained.

"The type of vaccine we want to introduce (before the antibodies appear) will take a little longer, but if we are able to validate [the Pre-POINT study], the larger efficacy trial will take about 6 years to do, so we are looking at 8 to 9 years before it could be available to everyone," he concluded.

The study was supported by grants from the Juvenile Diabetes Research Foundation, the Bundesministerium fur Bildung und Forschung, and the Deutsche Forschungs Gemeinschaft and by funding from the German Federal Ministry of Education and Research to the German Center for Diabetes Research. Lilly Pharmaceuticals provided the insulin crystals. Dr Bonifacio and colleagues report they have no relevant financial relationships. Dr Skyler is chair of the Type 1 Diabetes TrialNet Clinical Trials Network, which conducts studies aimed at prevention of type 1 diabetes, and is supported by the National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health.

JAMA. 2015;313:1541-1549, 1520-1521. Abstract, Editorial


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