Type II diabetes has a strong adversary in chemistry assistant professor James Hougland. Research conducted in his lab is aimed at developing new therapeutics to treat this all-too-common disease.
The American Diabetes Association granted Hougland a Junior Faculty Development Award in support of his research. The $414,000 grant will support three years of investigation into hormone interactions, which may lead to new diabetes treatments. “The research aims to develop a new biochemical avenue for treating type II diabetes,” he says.
More than 350 million Americans suffer from type II diabetes, also known as adult onset diabetes. The hallmark of the disease is resistance to insulin, an essential hormone responsible for metabolism of nutrients like glucose. When cells fail to respond to insulin, too much glucose remains in the bloodstream after digestion, and not enough is used to feed body cells. Because of this insulin resistance, many diabetic patients take insulin to try to normalize blood-sugar regulation.
Hougland is investigating a hormone called ghrelin, which may lead to a new line of therapeutics. Ghrelin plays a role in “how the body balances between taking in energy (as calories from food) and using that energy to support life,” Hougland says. Too much ghrelin can cause problems for insulin regulation. High levels of the hormone make insulin less effective at stimulating glucose movement from the blood to many body tissues. Because of this behavior, limiting ghrelin signaling could help diabetic patients more effectively regulate their blood-sugar by making insulin more effective.
There are a number of steps that lead to production of ghrelin—and Hougland aims to halt one. An enzyme called ghrelin O-acyltransferase, or GOAT, plays a crucial role in creating active ghrelin. GOAT acts by sticking a fatty acid tail onto ghrelin, which is an essential modification for ghrelin to control biological signaling. Stopping GOAT stops ghrelin action, which in turn could enhance insulin function in diabetics.
In order to stop ghrelin action, Hougland and his team are searching for small molecules to interrupt the GOAT-ghrelin binding process and fatty acid attachment to ghrelin. One approach they are employing is to do fine-scale chemical manipulations to both molecules and see how these changes influence binding. “We can then design new molecules that can mimic these interactions to block GOAT from binding and activating ghrelin,” Hougland says.
Another research angle involves screening libraries of already-existing small molecules to see which may be candidates for disrupting GOAT-ghrelin binding. Studies in the Hougland lab have already successfully identified several small molecules that effectively block GOAT from modifying ghrelin. “These two approaches—rational design and library screening—provide us the best chance for quickly finding GOAT inhibitors,” he says. After designing or finding GOAT inhibitors, Hougland will move the work into living cells, getting one step closer to finding new diabetes treatments.
While the development of new therapeutics maybe far off, Hougland stresses the importance of basic research and investigating the nitty-gritty of how body chemistry works. “Our work may hopefully lead to a new avenue for treating diabetes in the future. This shows how support from the American Diabetes Association and other funding agencies for basic research like ours, which complements translational and clinical studies, is vital to lay the foundation for novel disease therapies,” he says.