IMRIC Scientist and Alberta Collaborator Identify Key Trigger for Pancreatic Beta Cell Regeneration

Study reveals that a glucose-sensing enzyme signals the production of new insulin producing cells, suggesting a new path of treatment possibilities for type 1 diabetes

Based on the collaborative work done with Dr. James Shapiro, a world renowned researcher in islet transplantation for diabetes at the University of Alberta, Prof. Yuval Dor and colleagues have identified a key signal that prompts existing insulin-producing beta cells in the pancreas to form new beta cells in mice, a breakthrough discovery that may ultimately help researchers find ways to restore or increase beta cell function in people with type 1 diabetes.

Yuval Dor, Ph.D., a professor at the Institute for Medical Research Israel- Canada, the Hebrew University of Jerusalem, led the study which shows for the first time that a high rate of glucose metabolism, a process that converts glucose into energy that cells can use, triggers beta cells to regenerate. Coupled with a mechanism that prevents the immune system from attacking beta cells in the first place, the long-awaited finding may help pave the way to a full cure for type 1 diabetes. The study, which took five years to complete, was published in the April 6 issue of Cell Metabolism.

"Our work shows that as glucose is metabolized, it tells the beta cells to regenerate," says 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 that is the signal, but the glucose-sensing capacity of the beta cell that's key for regeneration."

In type 1 diabetes, the immune system launches a misguided attack on insulin-producing beta cells, resulting in their eventual loss and decline of function. Without insulin, the body's cells cannot absorb glucose from the blood and use it for energy. As a result, glucose accumulates in the blood, leaving the body's cells and tissues starved for energy. That's why people with the disease must inject insulin and monitor their blood glucose levels vigilantly every day, multiple times a day, to stay alive and maintain optimal health.

In their work, Dor and co-lead author Benjamin Glaser, M.D. of Hadassah Medical Center, 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 those mice with diabetes and elevated blood glucose levels had regenerated a greater number of new beta cells than mice without diabetes, suggesting that glucose is a key player in beta cell regeneration.

To determine how glucose plays a role in triggering beta cells to regenerate or proliferate, the researchers tweaked various steps in the glucose metabolism pathway within the beta cell. They found that an enzyme, glucokinase, which triggers the first step in converting glucose for energy, also stimulates beta cells to replicate.

"This means that the more work that beta cells are required to do, the more of themselves they make," says graduate student Shay Porat, who, along with Noa Weinberg, spearheaded the study. Because this study also showed that regeneration depends on glucokinase levels, rather than glucose levels, researchers may be able to use 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. The finding may pave the way for developing a new kind of drug or therapy to modulate glucokinase or other steps in the glucose-sensing pathway to direct beta cells down the path of regeneration and survival rather than death.

"This study shows that pharmacologic activators of glucokinase, a novel class of drugs being developed for the treatment of type 2 diabetes because of their ability to increase insulin production, also have the ability to increase beta cell replication," says Patricia Kilian, Ph.D., director for regeneration research at the Juvenile Diabetes Research Foundation International. "These or other drugs which affect glucose metabolism in the beta cell may have additional benefits for helping to restore beta cell function in both type 1 and type 2 diabetes. That's our hope."

Click here to read the summary of the article in the journal Cell Metabolism: "Control of Pancreatic β Cell Regeneration by Glucose Metabolism".

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