Ancient Genes May Lead to New Therapies for Diabetes

Debbie Thurmond, Ph.D.
Debbie Thurmond, Ph.D., studies proteins that have a long biological history.
“They’re an old gene family, ancestral,” said Thurmond, holder of City of Hope’s Ruth B. & Robert K. Lanman Chair in Gene Regulation and Drug Discovery Research and member of The Wanek Family Project for Type 1 Diabetes. “They’re in virtually every cell. Flies, worms and yeast all have them.”
Crucial to survival, the family of SNARE proteins are an essential part of the body’s complex transport system, helping to regulate diverse biological processes.
Thurmond investigates the role that certain members of that family play in metabolism — research that has the potential to result in new therapies for type 1 diabetes. And what she and her colleagues learn has implications for treating type 2 diabetes as well.

A Proverbial Shield

For the cell biologist, it starts with the health of insulin-producing beta cells, found in mini-organs called islets located in the pancreas. In type 1 diabetes, the immune system kills off beta cells, and her research points to a way to defend them.
“In the context of type 1 diabetes, we’re trying to keep the cells functioning, and we’re trying to put a proverbial protective coating over them,” said Thurmond, who also is founding chair of the Department of Molecular & Cellular Endocrinology and deputy director of the Diabetes & Metabolism Research Institute at City of Hope.
Thurmond’s research group has found that one particular SNARE protein, called syntaxin 4 or STX4 for short, is suppressed in type 1 diabetes. Inversely, they also have identified STX4 as a factor that can preserve the body’s own beta cells and deter the onset of the disease.
The team is pushing forward lab studies into technologies that use the protein’s power in order to treat type 1 diabetes. Building on a potential gene therapy platform that could stimulate the body to produce STX4, they are working on a cellular therapy that interferes with signaling that suppresses the protein.

The Power of Collaboration

Although the prospective therapies hold promise, Thurmond is aware that in type 1 diabetes, one must still contend with the autoimmune attack. So she has joined forces with Bart Roep, Ph.D., director of The Wanek Family Project, the Chan Soon-Shiong Shapiro Distinguished Chair in Diabetes, and professor and founding chair of the Department of Diabetes Immunology at City of Hope.
Together, the researchers are developing a combination treatment: Thurmond’s technology for stimulating STX4 plus Roep’s “immunosuppression-lite.” (Strong suppression of the body’s natural defenses would sabotage diabetes patients’ ability to ward off dangerous microbes and other threats.)
“Short-term in the lab, we can protect beta cell from immune attack with my technologies,” Thurmond said. “But when the immune system kicks into high gear, we’re guessing it’s probably going to be insufficient. Bart is really good at finding ways to ‘negotiate with the immune system,’ as he phrases it. The hope is that this will be a sustainable strategy for type 1 diabetes.”

Crossing Over

Fortunately, Thurmond’s approach also may provide an answer to type 2 diabetes, which is characterized by malfunctioning beta cells, as well as tissue in the body becoming insensitive to insulin.
“STX4 can resurrect a dying type 2 diabetic human islet,” she said. “That’s what I would consider a great therapeutic target.”
Because STX4 and related proteins fulfill numerous roles within the body, they are sometimes referred to as “multitaskers.” A second function of STX4 makes it especially promising for treating type 2 diabetes: It aids the body’s skeletal muscles in absorbing sugar, helping to reverse insulin resistance.
A 2015 laboratory study by Thurmond and colleagues highlighted some eye-opening possibilities. The scientists altered mice to overexpress STX4 in both the pancreas and the muscles. The difference was dramatic. The mice showed neither damaging effects from a high-fat diet nor age-induced insulin resistance. Though they grayed and gained weight in old age, they stayed livelier and lived far longer than their peers in the control group.
“People looked at the gene we focused on and said, ‘This has no implications in aging,’” Thurmond said. “But it does in metabolism. When you improve blood-sugar control, you are improving aging.”
Further experiments helped to tease out the positive effects of STX4’s role in beta cells versus muscle cells.
“The answer is, it’s both,” she said. “That’s why we work on multitaskers.”
To go from discovery to application, Thurmond is seeking the best way to deliver STX4 in the body. With its numerous functions, the protein might have negative effects if overexpressed systemwide. Thurmond plans to run an expansive set of tests to see how STX4 affects a variety of different cell types. The answers she finds ultimately could bring good news to people who face type 2 diabetes.
“There’s a lot of work to be done, but I’m very optimistic,” she said.


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