Peptide-based platform marks a major step toward needle-free diabetes care

For more than a century, oral insulin has been considered a "dream" therapy for diabetes, hindered by enzymatic degradation in the digestive tract and the absence of a dedicated intestinal transport mechanism. Consequently, many patients must rely on daily insulin injections, which can significantly reduce their quality of life.

A research team at Kumamoto University, led by Associate Professor Shingo Ito, has developed a breakthrough drug-delivery platform using a small-intestine-permeable cyclic peptide known as the DNP peptide, enabling efficient oral delivery of insulin.

Two complementary strategies for oral delivery

The researchers established two effective approaches to facilitate the intestinal absorption of insulin:

1. Mixing method (interaction-based): A modified "D-DNP-V peptide" was simply mixed with zinc-stabilized insulin hexamers. Oral administration to multiple diabetes models-including chemically induced (STZ mice) and genetic (Kuma mice) models-rapidly reduced blood glucose levels to the normal range. Consistent glycemic control was maintained with once-daily dosing for three consecutive days.
2. Conjugation method (covalent-based): Using click chemistry, the DNP peptide was directly conjugated to insulin to form a "DNP–insulin conjugate". This produced glucose-lowering effects comparable to the mixing method, confirming active peptide-mediated intestinal transport.

Overcoming the dose barrier

Unlike previous oral insulin approaches requiring very high doses (often over ten times that of an injection), this platform achieved a pharmacological bioavailability of approximately 33–41% relative to subcutaneous injection. This result demonstrates a substantial reduction in the amount of insulin needed for oral administration and marks a key step toward practical clinical use.

Perspective

"Insulin injections remain a daily burden for many patients," said Associate Professor Shingo Ito.

Our peptide-based platform offers a new route to deliver insulin orally and may be applicable to long-acting insulin formulations and other injectable biologics."

Shingo Ito, Associate Professor, Kumamoto University

The study was published in the international journal Molecular Pharmaceutics on November 24, 2025. The team is now progressing toward translational studies, including evaluations in large animal models and human intestinal systems.