A Well-Known Hormone Turns On Beta Cell Survival Genes

The key job of a beta cell is to respond to blood glucose levels to trigger insulin secretion. However, when things go awry as they do in T1D, and glucose levels are too high or elevated, the remaining beta cells can become “overworked.” What results is stress on the beta cell and the potential to form harmful particles known as free radicals—events that can result in beta cell death. A team of researchers at the Salk Institute for Biological Studies in La Jolla, CA, has now figured out how a well-known hormone can protect beta cells from the harmful conditions associated with T1D and prolong their survival. The work holds promise for several areas of T1D research, from improving drugs that stimulate beta cell survival to devising new anti-rejection drugs for transplants.

Researchers and pharmaceutical companies have long been interested in a hormone known as glucagon-like peptide-1 (GLP-1), because of its ability to make beta cells function better overall. In animal studies, not only can it enhance glucose-stimulated insulin secretion by beta cells, it can also enhance beta cell survival and proliferation.

However, until now, it wasn’t known in detail how GLP-1 actually works, mechanistically, to help regenerate beta cells in animals. The point is important to understand, since in people with type 2 diabetes, drugs that are forms of GLP-1 are used because of their ability to enhance insulin secretion, which results in improved blood glucose levels. However, an effect on beta cell regeneration in humans has not been demonstrated conclusively.

The new research findings provide a path for improving GLP-1 drugs to have greater effect on human beta cell survival and regeneration for both type 1 and type 2 diabetes. The study reveals the series of events that is set in motion inside the beta cell when GLP-1 latches onto its receptor on the cell’s surface.

In their work, lead researcher Marc Montminy, M.D., Ph.D., and his team treated beta cells with GLP-1 and then tracked the activity of the cells’ genes. To their surprise, they found that GLP-1 activates not one set of genes, as they previously thought, but two sets. The first set of genes becomes active shortly after GLP-1 docks onto its receptor. The second set of genes is activated hours after the first set turns off. This second set of genes is very interesting, because it is activated by hypoxia inducible factor 1α (HIF-1α), a genetic switch that is linked to cell survival.

“The HIF switch was previously known to help beta cells survive, but this is the first time that it has ever been linked to GLP-1,” says Dr. Montminy. “That’s the real accomplishment—it’s a connection that wasn’t evident before.”

The work may help improve the effects of a currently available drug called exendin-4, which is prescribed to people with type 2 diabetes to help their beta cells secrete insulin. The drug is a form of GLP-1.

Since activating HIF-1α may help beta cells survive, this work also has implications for islet transplantation. When islets are isolated outside of the body, they become less robust, so when they are transplanted back into the body, they need time to become healthy and strong again. Activating HIF-1α before islets are transplanted could help ensure that they flourish in their new home.

“These new insights could help research improve drugs that are used to treat type 1 and type 2 diabetes,” says Andrew Rakeman, Ph.D., senior program manager of beta cell therapies at JDRF. “By better understanding the mechanisms by which drugs like exendin-4 work, we have new strategies for prolonging the benefits that these drugs have on beta cell survival, and potentially for preventing beta cell loss.”