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Ultra-Rapid-Acting Insulin May Help Mimic Natural Insulin

By Andrew Curry , ,

Eric Andrew Appel, PhD
Photography by Nicki Appel

Eric Andrew Appel, PhD

Assistant professor of materials science and engineering at Stanford University

Insulin Action

American Diabetes Association Research Funding
Junior Faculty Development

For millions of people with diabetes around the world, manufactured insulin is a life-saving drug, replacing what their bodies aren’t able to produce.

Yet even though drug manufacturers have been making various insulin formulations for more than a century, science still hasn’t found a way to produce formulas that supply insulin to the body in a way that matches—or at least very closely mimics—what happens in the healthy human body.

When rising blood glucose levels signal the body’s beta cells to make insulin, the stuff is produced and secreted in minutes. Then it’s released into the bloodstream and does its job—namely, signaling to cells that they should quickly take up glucose from the bloodstream.

But insulin formulations face artificial conditions. For starters, they have to be kept in a form that’s chemically stable so they don’t break down during prolonged storage. Then they must be administered by injection into the skin instead of by direct secretion from the pancreas into the bloodstream.

Stabilizing agents, mainly the inactive chemical zinc, keep insulin from deteriorating while it’s stored on the pharmacy shelf. But they can also affect the absorption of the drug: Injected insulin appears in the bloodstream at a slower rate than insulin that’s secreted directly from the pancreas. This, in turn, leads to insulin lingering in the body longer than it normally would.

“If you have insulin on board and it’s acting for four to six hours, there’s an issue with patients going low three to four hours after a meal,” says Stanford University materials science and engineering professor Eric Andrew Appel, PhD. “There happens to be insulin on board, even when you don’t need it.”

That’s why the American Diabetes Association has given Appel a grant to help him engineer an ultra-rapid-acting insulin that starts working faster and, as a result, disappears from the bloodstream faster, too—all while remaining even more stable preinjection than state-of-the-art insulins on the market today. “If you were to have an insulin with faster onset as well as a much shorter [duration], it could be really beneficial,” says Appel.

The key, he says, is a new way to attach a chemical called polyethylene glycol (PEG). Insulin molecules form groups that stick together, slowing absorption from the injection site into the bloodstream. But PEG can get around that. “It’s a compound that provides a Saran wrap–like shield that prevents the [insulin] molecules from aggregating with their neighbors,” Appel explains. His innovation is a “molecular Velcro” that attaches PEG to the insulin in a new way. “As soon as you inject it, the protection falls off and you have free, authentic insulin able to go off and do its job.”

One of the most promising applications of this ultra-rapid-acting insulin would be in closed-loop insulin delivery systems, the continuous glucose monitor (CGM)–insulin pump combo sometimes referred to as an artificial pancreas. “Closed-loop devices work great at night but fail at mealtimes,” says Appel.

That’s because the body’s blood glucose is stable and predictable enough at night for a computer algorithm to manage. But the blood glucose peaks that come with meals require ultra-rapid insulin action for optimal glucose management.

Early results in animals have shown that Appel’s transiently PEG-based insulin formulations are much more shelf-stable than what’s on the market right now, lasting up to 10 times longer in the bottle or insulin pump than commercially available insulin.

Appel’s team is testing the insulin in pigs, and if his research shows that the PEG-formulated insulin is safe, he’ll go on to test it in humans. Ultimately, he hopes his approach could get artificial pancreas systems much closer to how the body’s natural insulin works. “Having insulin that turns on and off much faster allows the device to be much more responsive to the needs of the patient,” Appel says. “That means you can potentially have an autonomous device that can respond just like a real pancreas to whatever you eat.”

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