Insulin pill breakthrough could replace daily diabetes injections

Scientists have created an oral insulin pill, using a novel peptide system that lets insulin survive digestion and enter the bloodstream, potentially replacing daily injections for millions with diabetes

For more than a century, scientists have tried to create an insulin pill that could replace daily injections for people with diabetes. The challenge has been the same: the digestive system destroys insulin before it can reach the bloodstream. Now, researchers have developed a peptide-based delivery system that helps insulin pass through the intestinal wall and work effectively when taken orally.

Early results show promising glucose control and improved absorption, suggesting insulin tablets could become a realistic future treatment option.

The findings were published in the journal Molecular Pharmaceutics.

How the DNP peptide enables oral insulin delivery

Researchers at Kumamoto University, led by Associate Professor Shingo Ito, have developed a new approach to insulin treatment using a cyclic peptide, known as the DNP peptide, that passes through the small intestine. This allows insulin to be delivered orally, a feat not previously possible.

Normally, insulin can’t be taken as a pill because it’s a delicate protein that gets destroyed in the digestive system. When swallowed, stomach acid and digestive enzymes break insulin down into amino acids before it can reach the bloodstream. Even if some molecules survive, the intestinal wall blocks the absorption of large proteins like insulin, so almost none reach the blood. This is why oral insulin pills traditionally have near-zero effectiveness.

The researchers developed two methods to facilitate insulin’s passage across the intestinal barrier.

The first method was the mixing method (interaction-based), which combined a modified “D-DNP-V peptide” with zinc-stabilised insulin hexamers. When given orally to several diabetes models, including chemically induced (STZ mice) and genetic (Kuma mice), this mixture quickly lowered blood sugar levels to normal levels. Stable glucose control was maintained with once-daily dosing for three consecutive days.

The second was the conjugation method (covalent-based), using click chemistry, the researchers attached the DNP peptide directly to insulin, creating a “DNP-insulin conjugate.” This version lowered blood sugar just as effectively as the mixing method, confirming that the peptide actively facilitates insulin transport across the intestine.

Peptide platform makes oral insulin pills a possibility

One barrier to oral insulin pills is the need for extremely high doses, sometimes over ten times higher than injections. This new platform significantly reduces the required dose, achieving pharmacological bioavailability of about 33-41% compared to subcutaneous injection. That level of efficiency suggests oral insulin could become far more practical for real-world use.

“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.”

The researchers are moving forward with additional studies, including testing in larger animal models and systems that replicate the human intestine, as they work toward eventual clinical applications.