Insulin is a life-saving medication, helping to control blood sugar levels in diabetic patients. Although not a cure, this breakthrough has saved millions of lives, providing treatment for a disease that was previously considered a death sentence.

But a long-sought milestone in diabetes management has been replacing daily insulin injections with an oral medication.

“Insulin is currently administered through injections, which can be inconvenient for patients,” explained Jiangning Hu, professor at the National Engineering Research Center of Seafood, Dalian Polytechnic University, in an email. “The development of oral insulin drugs could provide a more convenient option for patients, enhancing their compliance and ease of use.” But this is easier said than done.

The problem with peptides

Insulin is a peptide, which means it is a molecule consisting of two or more amino acids linked in a chain. Peptides are found throughout the body and serve many important biological functions, and have many potential advantages when it comes to their applications as medicines.

The problem is their chemical nature poses limitations as drug candidates; namely, they are easily broken down under the acidic conditions found in the stomach, they aren’t absorbed well through the GI tract, and even when they do make it into the blood stream they are easily broken down and eliminated by the body’s enzymes.

This makes the current best option for diabetic patients to receive insulin via injection, which bypasses all these natural barriers. But this is not to say that researchers aren’t still thinking outside the box to come up with an oral alternative.

“Insulin injection requires patients to accurately determine the dosage of drugs and master injection techniques,” said Hu. “Otherwise, it can lead to fluctuations in blood sugar levels. The successful development of oral insulin drugs has the potential to significantly enhance the quality of life for patients with diabetes.

“With the availability of oral insulin, patients would no longer have to endure frequent injections, thereby reducing pain and discomfort,” he continued.

A self-assembling helix

Hu is part of a team of researchers who have been working toward this goal using nateglinide, an anti-diabetic drug normally used alongside insulin treatments to control blood sugar levels in patients with type 2 diabetes. Nateglinide works by stimulating the production of insulin in pancreatic beta-cells, which become damaged or dysfunctional in patients with diabetes.

“It is a complementary diabetes treatment,” explained Hu. “Compared to insulin, [which must be injected], nateglinide is an oral medication that can serve as an alternative or supplement to insulin therapy. It is particularly suitable for individuals with type 2 diabetes who experience high blood sugar levels after meals and need to reduce their blood sugar levels.”

But nateglinide can be tricky as taking it at the wrong time could result in increased blood sugar fluctuations and sudden low blood sugar referred to as hypoglycemia, which can be life threatening.

Hu says that he and his team were inspired by the ability of peptides that contain six-membered phenyl rings, such as D-phenylalanine, to self assemble into more complex structures based on weak bonds that form between these and other chemical groups in the molecules. The formation of the DNA double helix is a prime example of how small molecular building blocks spontaneously organize to form a larger complex structure.

Nateglinide provides a protective coating

Since nateglinide is a D-phenylalanine derivative, Hu says they developed the idea to use it as a self-assembling protective carrier for insulin to keep it safe from the stomach and GI tract.

But when nateglinide self-assembles on its own, it forms a clear solution, which wasn’t what the team was initially hoping for. “We wanted to develop a gel-like coating that could act as the oral medication’s protective barrier,” said Hu.

Serendipitously, when small amount of calcium cations were added into the solution, a milky gel did form. This was not observed in the self-assembly of the diphenylalanine peptide as well as other peptides they tested, which Hu attributes to a carbon ring found in nateglinide, which helps to slightly impede the self-assembly in the presence of the cations, bringing it slightly out of solution.

Using advanced microscopy, the team were able to determine that the self-assembled natelinide fibers were arranging themselves into a left-handed helical structure, which they coated on the surface of alignate microgels that had been filled with insulin. “This coating provided a more effective encapsulation of insulin compared to the microgel alone,” said Hu.

The team monitored the sustained release and prolonged circulation of insulin and natelinide from their loaded microgels in the intestinal tract.

“They synergistically maintained a relatively normal blood glucose level and restored the function of damaged pancreatic islets in […] diabetic mice after oral administration once every three days,” he explained. “The 90-day tests […] showed no signs of toxicity and exhibited excellent biocompatibility when administered orally.”

The trouble with the insulin market

Although insulin was developed over 100 years ago as a treatment for diabetes and the patent was sold by its inventor for just $1, current prices for insulin medications in the United States have reached critical levels.

A 2017 article published in The New York Times showed that between 2002 to 2013, the prices of the most popular insulin products tripled, with some costing up to $900 per patient per month.

“These high prices have devastating consequences for patients,” wrote Ryan Knox, a senior research fellow at the Solomon Center for Health Law and Policy at Yale, in the Journal of Law and Bioscience. “One in four people with diabetes in the United States ration their insulin, which can lead to severe complications and even death.”

Andrew Pospisilik, who was not involved in Hu’s study, is a professor in the Department of Epigenetics at the Van Andel Institute and an expert in functional genetics, complex disease biology, and epigenetics, with a focus on metabolic disease such as diabetes and obesity. He sees this barrier to competition as a possible hurdle facing Hu’s oral delivery platform.

“Simply put, [an oral diabetes medication] would avoid the need for self injections and therefore comes with improved compliance, patient standard of care and comfort (particularly with children), [as well as] reduced biohazard waste,” Pospisilik explained. “Whether large pharma companies that dominate this market want this to become a real therapy or not, for their myriad patent [and] business interests, will determine if this approach will or will not succeed — in addition of course to the quality of the technology itself, patient responses, safety profiles, outcomes of clinical trials.”

Although the initial tests have shown promise and Hu remains optimistic, they readily acknowledge that there are still hurdles to overcome and unanswered questions that need addressing before clinical trials — something they’re keen to soon pursue.

Hu emphasized that the team want to make a difference for patients. In their quest to make a real impact, they are not only advancing our knowledge but also propelling society forward into a brighter, healthier future.

Reference: Jiangning Hu, et al., Helical-Like Assembly of Nateglinide as Coating for Oral Delivery of Insulin and Their Synergistic Prevention of Diabetes Mellitus, Advanced Science (2023). DOI: 10.1002/advs.202301879

Feature image credit: The-Lore on Unsplash