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January 20, 2015
CHAPEL HILL, NC – Zhen Gu, PhD, assistant professor in the UNC-NCSU joint department of biomedical engineering, has received a $1.625 million, five-year “Pathway to Stop Diabetes” Research Award from the American Diabetes Association.
Gu will use the funds to create synthetic versions of beta cells, the body’s natural insulin-producing factories. Beta cells store and release insulin to help the body process blood sugar that builds up in the bloodstream after a meal. In people with diabetes, these cells are either damaged or unable to produce enough insulin to keep blood sugar levels under control.
As a result, patients with type 1 diabetes and advanced type 2 diabetes must regularly monitor their blood sugar and inject themselves daily with varying amounts of insulin. The process is painful and imprecise, and injecting too much or too little medication can lead to disastrous consequences such as seizures, brain damage, and death. According to the International Diabetes Federation, diabetes caused 4.9 million deaths in 2014 alone.
For the last four years, Gu has explored other ways to deliver insulin. Thus far, he has tested half a dozen ideas, including tiny capsules made from shrimp shells and seaweed and painless microneedle patches. Each approach has provided an incremental improvement over the last, but nothing has performed as well as healthy beta cells. Therefore, for his latest endeavor Gu will try to follow nature’s lead to engineer the perfect insulin delivery vehicle. The new approach is part of an emerging field called biomimetics, which adapts designs from the natural world to address modern problems.
“We want to synthesize molecules that mimic virtually every aspect of beta cells using the chemicals we have in our toolbox,” said Gu, a member of the UNC School of Medicine, the UNC Eshelman School of Pharmacy, and the UNC Diabetes Care Center. “Nobody has ever tried to do this before. I admit, it might seem like a crazy idea.”
Beta cells cram a lot of functions into a small package. They act both as factories and as warehouses, making and storing insulin in tiny sacs called vesicles. They also act as alarm call centers, sensing increases in blood sugar levels and signaling vesicles to release insulin into the bloodstream. Gu is trying to replicate these functions through what he calls “intelligent insulin nanoparticles.”
As a first step, Gu used a $50,000 pilot grant from the North Carolina Translational and Clinical Sciences (NC TraCS) Institute to show that he could create structures with the same sugar-sensing, insulin-releasing properties as vesicles. Vesicles are typically bordered by a double layer of membranes, which ensure that only specific molecules can get in or out. Gu used two types of biocompatible and biodegradable materials to encase his artificial vesicles. The first was polyethylene glycol or PEG, a polymer that is often used in medicines. The second was a modified version of polyserine, a string of one type of the 20 amino acids that are the building blocks of proteins.
By connecting the two, Gu was able to create a new molecule with one end that is water-loving or hydrophilic and one that is water-fearing or hydrophobic. Much like the coalescing of oil droplets in water, a mixture of these molecules will self-assemble into a bilayer membrane with the hydrophobic ends pointing inward and the hydrophilic ends pointing outward. The resulting vesicles are only 100 nanometers in size, or 1000 times smaller than the width of a human hair.
Within each nanovesicle, Gu inserts a core of solid insulin and specially designed enzymes that are sensitive to glucose. When blood sugar levels increase, glucose crosses the membrane of these artificial vesicles, as its neutral charge allows it to do, and is converted by the enzymes into gluconic acid. In turn, the inside of the vesicles become acidic, degrading the bilayer shell to release insulin into the bloodstream.
In a paper published last year in the journal Biomacromolecules, Gu showed that a single injection of these nanovesicles under the skin of diabetic mice kept blood glucose levels in the normal range for up to five days. He plans to use the ADA funding to optimize these vesicles and create new ones that could last even longer, from a week to even a month after injection.
“Right now, the vesicles release the drug and then gradually disappear. Eventually, we would like to design vesicles that could do this over and over again. After they release insulin and while the glucose levels are going down, the vesicles could self-heal to keep the rest of the insulin inside, and then wait for the next event,” said Gu.
As an added precaution, Gu is working on nanovesicles that contain a hormone called glucagon, which is the antidote to insulin. In the unlikely event that the insulin-containing vesicles discharge too much of their cargo, these glucagon-containing vesicles can release glucagon to raise glucose levels back to safe levels.
“It is so exciting that the ADA has made this investment in Dr. Gu’s revolutionary work,” said John Buse, MD, PhD, a collaborator of Gu’s and director of the UNC Diabetes Care Center. “There is a long way to go before we are ready for human studies, but we can’t get there if we do not start here.”
Gu will test all these approaches in large animal models of diabetes, with that ultimate goal of pushing the technology into clinical trials.
“I get emails on a regular basis from patients who are checking on my research and are eager to help me test this approach once it is ready,” said Gu. “My grandmother died from diabetes, and I have several relatives still living with the disease. For me, this work is not about publishing papers and getting patents, it is about helping people.”
Gu is one of six awardees out of the 116 nominated to receive funding through the second round of the ADA’s Pathway to Stop Diabetes initiative. The awardees are selected through internal competition at U.S. academic and nonprofit research institutions, which identify and nominate their most creative and talented scientists. The nominated scientists, who are either just starting their careers in diabetes research or who are already established in another field but want to expand their focus into the area, propose innovative ideas for diabetes research projects. Over the next decade, the ADA pledges to fund a total of 100 new diabetes researchers.