Key Enzyme Boosts Beta Cell Numbers

JDRF-funded researchers have identified a key signal that prompts existing beta cells, the only cells in the body that produce the hormone insulin, to form new beta cells. Their breakthrough discovery may ultimately be used to develop new treatments that will help to increase the number or function of beta cells in people with type 1 diabetes.

The work, led by Yuval Dor, Ph.D., a professor at the Institute for Medical Research Israel-Canada, The Hebrew University of Jerusalem, shows for the first time that a key enzyme known as glucokinase helps boost the number of beta cells in the pancreas. The study, which was conducted with mice, showed that increasing glucokinase activity causes these beta cells to multiply and regenerate in the pancreas. This enzyme, which is found in beta cells, is responsible for sensing glucose in the blood and secreting insulin in response to glucose levels. This new study shows that glucokinase not only plays a role in beta cell function, as described above, but it also regulates beta cell growth.

“Our work shows that as glucose is metabolized, it signals the beta cells to multiply,” says Dr. Dor, who is also a 2010 recipient of the JDRF Gerold and Kayla Grodsky Basic Research Scientist Award. “It’s not blood glucose per se, but the glucose-sensing capacity of the beta cell—glucokinase—that’s key for regeneration.”

In their work, Dr. Dor, along with co-lead author Benjamin Glaser, M.D., of Hadassah Medical Center, also in Israel, used a genetic system to destroy 80 percent of the insulin-producing cells in adult mice, rendering the mice diabetic. When the researchers compared these mice with control mice, they found that the diabetic mice, which had elevated blood glucose levels, regenerated a greater number of new beta cells than mice without diabetes. This finding suggests that the level of glucose detected by the beta cell was somehow involved in the production of more beta cells.

To find out exactly how glucose was involved, Drs. Dor and Glaser, along with graduate students Shay Porat and Noa Weinberg, tweaked various steps in the glucose metabolism pathway. They found that beta cells replicate as long as they sense glucose and secrete insulin. “We can manipulate beta cells with a drug to increase glucokinase activity but without relying on the presence of high levels of glucose, which are unhealthy,” says Dr. Dor. “We can stimulate the beta cell to regenerate by tricking it into thinking that glucose levels are high.”

Because this study shows that regeneration depends on changes in glucokinase activity, rather than glucose, researchers may be able to use glucokinase-stimulating drugs to trigger beta cells to regenerate without exposing the body to elevated glucose levels, which can cause organ damage and even kill beta cells. “Currently, drugs that activate glucokinase are being developed for the treatment of type 2 diabetes because of their ability to stimulate insulin secretion,” says Patricia Kilian, Ph.D., director for regeneration research at JDRF. “Our hope is that they will also be able to increase beta cell functional mass to treat type 1 diabetes.”