Pharma Quest

New compounds under development at NC Central University’s Biomanufacturing Research Institute and Technology Enterprise (BRITE) could be key to creating a better treatment for diabetes.

“I have the benefit of sitting down and seeing what these molecules look like,” says Dr. Jonathan Sexton, as he pulls small trays out of metal storage units that sit on the shelves of giant freezers. “We are trying to make sense of these molecular structures—to see what they look like and try to figure out which one is going to be the best.”

Dr. Sexton is hoping some of those molecules become a new treatment for diabetes. He’s in charge of one of the labs at North Carolina Central University’s BRITE, which stands for Biomanufacturing Research Institute and Technology Enterprise.

Those freezers contain 460,000 molecular compounds. For the past six years Dr. Sexton and his team have worked to develop a drug treatment for non-alcoholic fatty liver disease. It’s the most chronic liver disease in adults and children, and one that affects the majority of patients with type 2 diabetes.

It’s a search for a drug that could have significant impact on diabetes patients' health, but it’s also a pharmaceutical search for a needle in a haystack.

“Essentially, we take cells from a human liver and we’ll plate them in dishes with 96 or 384 plates and then we will add a potential drug—or a drug-like molecule—to see if it has a positive or negative effect, or no effect at all,” says Dr. Sexton.

Dr. Sexton depends on technology to help with that 'needle in a haystack' search for a new drug to improve insulin resistance in the liver. The technology is eye-opening. It allows researchers to observe the body’s chemical workings at the cellular level. An image of the pancreas is pulled up on the screen of a flouresence microscope.

“I know this looks like a battlefield map with lots of bright red blotches all over but these are human beta cells,” explains Dr. Sexton, as he moves the cursor over the screen. “That granular pattern in the blotch is actually insulin and you can move around and find areas that are filling with insulin.”

Insulin is a hormone that controls blood glucose levels. The pancreatic beta cells release packets of insulin into the blood whenever blood glucose levels spike, usually after a meal. A screen shot of the same cells after a meal shows a stark difference. The blotches are not as bright and the yellow specks inside the cells are almost gone.

“If it looks like the cells are empty, you’re right,” says Dr. Sexton. “This is right after a meal and these cells have released their insulin and you can visually see what the difference is."

But while the cells look depleted, if you look closely there is a small yellow dot in the middle of almost every cell. It’s called the depletion pool and it is freshly synthesized insulin that will soon be released if it is needed.

But individuals with sedentary lifestyles and poor diets strain those beta cells because their bodies are taking in too much glucose. Type 2 diabetes develops when the cells become overused and can’t handle increasing blood sugar levels. 

Researchers in Dr. Sexton’s lab are searching for compounds that can regulate insulin secretion in a glucose-dependent manner. In other words, applying a drug to the beta cells so that insulin would only be released in high glucose situations. That would help prevent the cells from becoming overused.

Researchers say they’ve discovered several compounds that show promising results in tests on mice. Senior Alex Beasley was cured of diabetes after changing his lifestyle by eating better, exercising and losing weight. But he has friends who have not been so lucky and knows his work in the lab could help them.

“I have friends who are diabetic who are regular size, not obese or anything, and it’s not their fault that they are diabetic," says Beasley. “It would be great if I could help them and they wouldn’t have to get shots.”

The work at BRITE mirrors what is happening nationwide in the drug development field. Pharmaceutical companies are relying on universities to not only discover new drugs but also do the early stage testing of new drugs. Sexton admits that puts a lot of pressure on researchers, but it also opens up opportunities.

“The obesity epidemic and the diabetes epidemic are creating a big unmet medical need and there is no curative therapy for those diseases,” explains Dr. Sexton, as he readies another tray of cells to study. “And while the approach we are using—a brute force approach—screening a lot of compounds to discover molecules that are interesting, it’s a starting point. But then we have to go through the rational drug design process of testing and retesting to make sure those compounds that are interesting do, in fact, work.”

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