medwireNews: Giving oral insulin to children at genetic high risk of diabetes stimulates a regulatory immune response without inducing hypoglycaemia, show the findings of the Pre-POINT study.

Pre-POINT was a double-blind, placebo-controlled trial that investigated oral insulin doses ranging from 2.5 to 67.5 mg for up to 18 months.

The highest dose was the most effective, with 83.3% of children given this dose developing an antibody or T-cell response, compared with between 16.7% and 33.3% for lower doses and 20.0% for placebo.

“The immune response observed in insulin-treated children did not display the features typically associated with type 1 diabetes, such as a dominant proinflammatory IFNG CD4+ T-cell response”, Ezio Bonifacio (DFG Center for Regenerative Therapies, Dresden, Germany) and study co-authors write in JAMA.

A total of 25 children, aged between 2 and 7 years, participated in the trial. They had no autoantibodies to glutamic acid decarboxylase (GAD)65 or insulinoma-associated antigen (IA)-2, but did have two first-degree relatives or a sibling with Type 1 diabetes, and also a high-risk human leukocyte antigen haplotype.

Ten children received placebo and 15 were given oral insulin, with nine receiving a dose escalation. Among the six children who received the highest dose (67.5 mg/day), three had increased serum immunoglobulin (Ig)G binding to insulin, and two had a T-cell response to insulin and two to proinsulin.

Changes in the gene expression of insulin-responsive T cells showed a profile typical of FOXP3+ regulatory cells. The ratio of FOXP3+ cells to pro-inflammatory interferon-γ–releasing T cells was 1.05 for insulin-responsive cells and 1.15 for proinsulin-responsive cells, compared with a reported ratio of 0.26 in proinsulin-responsive T cells in islet cell autoantibody-positive children.

None of the patients displayed symptoms of hypoglycaemia after taking insulin, and none of the children developed GAD65 or IA-2 autoantibodies during follow-up, which ended 12 months after dose escalation.

However, editorialist Jay Skyler (University of Miami Miller School of Medicine, Florida, USA) observes that the trial participants were past the age of peak islet cell autoantibody incidence, which is between 6 months and 2 years.

“It is possible that the study included a survivor cohort that was antibody-negative because the participants had already passed the period of likely seroconversion”, he says. “Consequently, to avoid missing enrollment prior to seroconversion, a definitive trial would need to enroll individuals younger than 1 year.”

By Eleanor McDermid, Senior medwireNews Reporter

JAMA 2015; 313: 1520–1521, 1541–1549

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