Infant islet autoantibody development not prevented by daily oral insulin

medwireNews: High-dose, daily oral insulin does not prevent the development of islet autoantibodies in infants with an elevated genetic risk but may delay progression from autoantibody development to diabetes, show findings from the Primary Oral Insulin Trial (POInT).

Although there was no benefit on the development of islet autoantibodies overall, the researchers report in The Lancet that the impact of daily oral insulin varied by genotype in the INS type 1 diabetes susceptibility gene.

Bart Roep, from Leiden University Medical Center in the Netherlands, says in an accompanying comment that this highlights an “opportunity and necessity for personalised immune prevention or intervention therapy in type 1 diabetes.”

He continues: “With a better definition of increased genetic risk valuing INS variation, this personalisation may be easily implemented.”

Of 241,977 newborns who were identified through the Global Platform for the Prevention of Autoimmune Diabetes genetic screening programs in Germany, Poland, Sweden, Belgium, and the UK, 2750 (1.1%) had a predicted genetic risk of greater than 10% for developing two or more islet autoantibodies by age 6.5 years.

The researchers randomly assigned 1048 of these infants (51% boys) at a median age of 6 months to receive oral insulin manufactured from recombinant human zinc–insulin crystals (n=526) or placebo (n=522) until age 3 years. Individuals given insulin began at a once-daily dose of 7.5 mg for 2 months, increasing to 22.5 mg for 2 months, and then 67.5 mg until age 3 years.

Anette-Gabriele Ziegler (Technical University of Munich, Germany) and co-investigators report that 10% of participants in the insulin group and 9% of those in the placebo group reached the primary outcome of two or more islet autoantibodies or diabetes during a median 4 years of follow-up, a nonsignificant between-group difference.

There was also no significant difference between the insulin and placebo groups in the number of participants who developed one or more islet autoantibodies (13 vs 10%), or who were diagnosed with diabetes or dysglycemia (3 vs 5%).

However, further analysis indicated that oral insulin use was associated with significantly slower progression to clinical (stage 3) type 1 diabetes. Indeed, the 3-year diabetes-free survival rate was 63.2% in the insulin-treated participants and 35.5% in the placebo-treated participants, while the annualized progression rate from the development of two or more islet autoantibodies to diabetes was 16.6% and 29.4%, respectively.

Ziegler and team also observed an interaction between insulin treatment and the INS rs1004446 genotype. Among individuals with the INS CC genotype, which is linked to increased diabetes susceptibility, the risk for developing dysglycemia or diabetes was a significant 0.38-fold lower in the insulin group relative to the placebo group, with a 5-year probability of 3.5% versus 10.1%.

Conversely, among individuals with the INS CT and TT genotypes, which are not linked to increased susceptibility to diabetes, the risk for developing two or more islet autoantibodies was a significant 2.10-fold higher in the insulin group relative to the placebo-group, at 5-year probabilities of 12.8% and 7.1%, respectively.

“This pharmacogenetic interaction, therefore, identifies a subgroup that could benefit from primary oral insulin therapy and a subgroup that does not benefit and in whom exposure might increase autoimmunity,” the authors remark.

They point out that “the intervention was well tolerated,” with no adverse metabolic effects on glucose levels. Of the 10,252 reported adverse events, 49.5% occurred among participants given oral insulin group and 50.5% occurred in those given placebo.

Ziegler et al suggest that the lack of efficacy with insulin “could be due to incorrect assumptions regarding the importance of insulin as an autoantigen in the disease process, or suboptimal dose, timing, route, or formulation of insulin administration.”

Nonetheless, they say their study “provided evidence that the treatment elicited changes in the natural course of the disease” and showed that “the novel pharmacogenetic interaction supports the concept of personalised antigen-specific therapy based on a priori genetic selection for susceptibility to insulin autoimmunity.”

medwireNews is an independent medical news service provided by Springer Healthcare Ltd. © 2025 Springer Healthcare Ltd, part of Springer Nature

Lancet 2025; doi:10.1016/S0140-6736(25)01726-X
Lancet 2025; doi:10.1016/S0140-6736(25)02005-7