UC San Diego Health Sciences News

In this photomicrograph of a sliced rat beta cell, insulin granules are the dark black spots surrounded by a white area called a “halo.” The colored borders around the granules are added to help identify and classify them. (Photo courtesy of Tim McClanahan/NASA)

A brain protein with surprising links to diabetes

Neurexins are proteins that help glue neurons together, connecting the latter at their synapses where they help mediate signaling and nature of neural networks. In 2008, Steven Chessler, MD, PhD, an associate professor of medicine in the UC San Diego School of Medicine and Pediatric Diabetes Research Center, and colleagues discovered that neurexins weren’t limited to the central nervous system. They also resided in pancreatic islet beta cells, cells in the pancreas that make, store and release insulin, a crucial hormone that controls blood sugar levels.

It’s the destruction or dysfunction of these beta cells that is central to diabetes, a group of chronic metabolic disorders that has reached epidemic proportions in the United States: Almost 26 million Americans have a form of diabetes (mostly type 2), with an estimated 79 million more considered to be pre-diabetic.

For researchers like Chessler, the next step was to figure out neurexins did in beta cells. They have. In a paper published in The Journal of Biological Chemistry, senior study author Chessler and colleagues report for the first time that neurexins appear to help modulate the release of insulin from beta cells. The discovery suggests the proteins might be a new and promising target for new diabetes therapies.

“The beta cells package newly-made insulin into ‘granules,’” said Chessler. “When necessary, the granules move to the cell surface to empty their cargo of insulin into the bloodstream. Neurexin creates ‘docking sites’ where the granules pause just beneath the cell surface.”

From these docking sites, the granules are poised to quickly merge with the cell membrane and release insulin into the circulation. But the sites also represent a key place to block the release of insulin.

“This is likely a safety brake: a last-minute chance for the beta cell to stop the granules in their tracks and prevent too much insulin release. Too much insulin is dangerous because it can cause hypoglycemia,” Chessler said.

The docking sites are constructed of multiple, different proteins. As with neurons, neurexin seems to be the glue, grouping the proteins together beneath the beta cell membrane. Unlike the other proteins, however, neurexin extends through the membrane to the cell’s outer surface, which means it can detect and react to the cell’s surroundings and external stimuli.

“Its presence on the cell surface makes it accessible to biotherapeutic agents,” said Chessler. “Biotherapeutic agents or, alternatively, small molecules influencing neurexin function, could help overcome the impaired insulin secretion that is seen in type 2 diabetes. By tilting the balance away from ‘braking’ and more towards insulin release at docking sites and/or by influencing the number of docking sites, these therapeutic agents could perhaps significantly improve beta cell function in type 2 diabetes.”

Importantly, Chessler added that such a therapy would likely not increase the risk of hypoglycemia, a significant complication with current treatments.
The JBC paper may be just the beginning of research revealing neurexins’ surprisingly important and widespread utility. Chessler noted that neurexin mutations are known to underlie some cases of schizophrenia, autism and other mental disorders.

“Our findings could help explain the known link between schizophrenia and autism and their increased risk for diabetes,” he said.

Co-authors of the paper with Chessler are Merrie Mosedale from the UC San Diego Pediatric Diabetes Research Center, UCSD Department of Medicine and Biomedical Sciences Graduate Program, Sonya Egodage and Rei C. Calma in UCSD School of Medicine Department of Medicine and Biomedical Sciences Graduate Program and Nai-Wen Chi at the UCSD Department of Medicine, Biomedical Sciences Graduate Program and Research Service, VA San Diego Healthcare System.

Funding for this research came, in part, from the National Institutes of Health, the Juvenile Diabetes Research Foundation and the UC San Diego Graduate Training Program in Cellular and Molecular Pharmacology.