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Researchers formulate new ultrafast insulin

Stanford University bioengineers are developing a faster-acting formulation of insulin that can help diabetes patients better regulate their blood sugar levels.

Harnessing some materials science "magic," Stanford researchers are developing a new formulation of insulin that could become active four times faster than current fast-acting insulins.

If proven effective, the formulation could be a boon for diabetics who carefully coordinate the timing of insulin with certain activities -- such as eating -- that can cause their blood sugar levels to fluctuate. One particularly challenging aspect of this coordination is the duration of insulin's activity in the body: there is a delay in how quickly it gets to work, and it remains active for several hours.

As I wrote in a Stanford News Service article:

The researchers focused on so-called monomeric insulin, which has a molecular structure that, according to theory, should allow it to act faster than other forms of insulin. The catch is that monomeric insulin is too unstable for practical use. So, in order to realize the ultrafast potential of this insulin, the researchers relied on some materials science magic.

Fixing the stability problem

The Stanford scientists' key innovation was developing a polymer that could be added to the formulation to stabilize monomeric insulin, which readily absorbs into the bloodstream but becomes inactive after only one to two  hours in a vial.

The researchers presented their formulation in a paper published July 1 in Science Translational Medicine.

"The insulin molecules themselves are fine, so we wanted to develop a 'magic fairy dust' that you add into a vial that would help to fix the stability problem," Eric Appel, PhD, assistant professor of materials science and engineering at Stanford, said in the News Service article.

"People often focus on the therapeutic agents in a drug formulation but, by focusing only on the performance additives -- parts that were once referred to as 'inactive ingredients' -- we can achieve really big advancements in the overall efficacy of the drug," said Appel, senior author of the paper.

Finding the magic polymer

Individual molecules of monomeric insulin become inactive if they interact with each other, making it a problem that the molecules are attracted to the surface of the liquid in a vial and clump together there.

So, looking to keep the monomeric insulin active, the researchers searched for an additive -- specifically a polymer, defined as a large molecular substance made up of tiny molecules called monomers -- that could get to the surface first to prevent the monomeric insulin from clumping.

Conducting three weeks of high-throughput screening in Australia, the scientists created a library of 1,500 candidate polymers. Then, back at Stanford, they began processing and testing those candidates by hand to see if any of them exhibited the desired stabilizing behavior. The first 100 had no effect.

"It was this moment when it felt like you had traveled halfway across the world and spent countless hours in the lab only to have no benefit whatsoever," said Joseph Mann, a graduate student in the Appel lab and co-lead author of the paper. "I walked into Eric's office and I asked him, 'When is it an appropriate time to call this project off?'"

Appel reassured Mann that other candidates still had promise, and their magic polymer was soon found.

Testing the formulation

In accelerated aging tests, the polymer extended stability of commercial insulin from about 10 hours to upwards of a month. In the same tests, the polymer stabilized monomeric insulin for more than 24 hours.

"In terms of stability, we took a big step backward by making the insulin monomeric. Then, by adding our polymer, we met more than double the stability of the current commercial standard," said Caitlin Maikawa, a graduate student in the Appel lab and co-lead author of the paper.

Next, the researchers tested the monomeric insulin formulation in diabetic pigs. They found that it reached 90% peak activity within five minutes after injection and peaked at 10 minutes. Commercial fast-acting insulin, by contrast, began showing significant activity after 10 minutes and peaked at 25 minutes.

In humans, this difference could translate to a four-fold decrease in the time insulin takes to reach peak activity. The monomeric insulin finished its activity sooner as well -- quick action such as this could make it easier for people to manage their blood sugar levels.

The researchers plan to apply to the U.S. Food and Drug Administration for approval to test their insulin formulation in clinical patient trials. They are also interested in other applications of their stabilizing polymer, and in whether their monomeric insulin formation could aid the development of an artificial pancreas.

Image by Chinnapong

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