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Duke researchers see potential for longer-lasting diabetes drug

Researchers in Duke University’s engineering school say they’ve managed to refine one of the treatments for type 2 diabetes, showing there might one day be a way to tailor it so a patient can go a month between injections.

The team, centered in Pratt School of Engineering professor Ashutosh Chilkoti’s lab, on Monday published a journal article reporting that its strategy for controlling the release of a molecule that signals the body to produce insulin seems to better the results of existing FDA-approved drugs that are effective for only up to about a week.

Compared to some alternatives, it’s also “quite easy to produce and quite easy to purify,” potentially offering lower-cost treatment options that would improve health care in developing countries, said Kelli Luginbuhl, the Ph.D. student Chilkoti credits with doing the key work on the project.

In its article in the journal Nature Biomedical Engineering, the team explained that it’s trying to improve the delivery into the bloodstream of molecules called GLP1 – that’s glucagon-like peptide-1, to the biochemists among us.

Normally produced in the large intestine, the amino acid signals the pancreas to release insulin, but only does so when the body’s blood-sugar levels are running at a certain level.

“They only promote insulin release when the body needs it,” Luginbuhl said.

Pharmaceutical scientists have known about the substance and its potential benefits since the 1980s. Several companies, GlaxoSmithKline and Eli Lilly most notably, have managed to develop and bring to the market anti-diabetes drugs that use it.

But the problem scientists have needed to overcome is that GLP1 has a short half-life in the body. It can break down in minutes, thanks to action of the body’s cells and kidneys. Existing drugs extend its life by bonding it with microscopic particles or antibodies, but that approach is hitting a point a diminishing returns, Luginbuhl and her colleagues argue.

Chilkoti, however, is the inventor of a Duke-licensed technique for facilitating drug delivery that uses another organic molecule that can be synthesized in E. coli bacteria. Its most important property is it reacts to temperature, remaining water-like at room temperature but turning to a gel as conditions get warmer.

That in this case is the key to controlling the pace of a drug’s release. Luginbuhl and her colleagues say they’ve shown it’s possible to customize a mix of the two molecules to react specifically to body heat. They’ve tested the idea in mice and monkeys. In mice, the fusion of the two seems to control glucose for up to 10 days. In monkeys – macaques, specifically – it lasted for at least 17 days.

Once it changes into a gel, the mix releases GLP1 slowly. And given how metabolism scales with size, it’s possible that in humans the combination “could provide for three weeks” of blood-sugar control in humans and perhaps even become a “one-monthly option for diabetic patients,” the team said in its article.

Though GLP1-based drugs remain “second- or third-line options” presently for Type 2 diabetes, they’re promising for their potential to simplify the treatment regime for some patients and deal with some of its side effects, Luginbuhl said.

For Luginbuhl, the project is basically the outcome of about five years of work on her Ph.D., and started with a suggestion from Chilkoti that she look into some of the characteristics of the state-changing molecule.

Originally, that was “supposed to be a quick question to answer to learn the ropes in the lab my first year,” and the work initially produced “disappointing results in mice,” she said.

But Luginbuhl said she “got hooked” on the idea, and decided to see what would happen “if we optimized every part” of the process of creating the mix.

Despite the project’s outcome, it’s not clear yet that the team – which also includes Duke researchers Jeffrey Schaal, Eric Mastria, Xinghai Li, Samagya Banskota, Mark Feinglos and David D’Alessio – can eventually take the step of seeing how its ideas might work in humans.

The company that holds the license to Chilkoti’s technique has tried working with GLP1 before, but it didn’t end up with a drug that worked quite as well as others in what it terms “the competitive environment for the treatment of type 2 diabetes.” Nowadays it focuses mostly on applying the technology to heart disease. The professor’s looking around overseas for potential investors in anti-diabetes work.

Ray Gronberg: 919-419-6648, @rcgronberg

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