How a 'moonlighting' protein could change how we treat Type 2 diabetes

A protein that helps neurons grow also holds down a second job, this one outside the nervous system: It triggers release of insulin that helps us maintain a normal level of blood sugar.

The discovery of the protein’s moonlighting gig could potentially lead to new approaches for treating type 2 diabetes, the form of the disease in which the body does not make effective use of the insulin it produces.

The jumping off point for the research was scientists’ knowledge that neurons—which carry signals in the brain and nervous system—have similarities in molecular makeup and signaling receptors to beta cells in the pancreas, where insulin is produced.

Researchers in the Johns Hopkins University lab of Rejji Kuruvilla noted that pancreatic beta-cells have receptor proteins called neurotrophins, including one called nerve growth factor. In previous work, Kuruvilla has studied NGF’s role in nurturing neuron growth.

“This project was sparked by seeing NGF receptors present in beta-cells,” says Kuruvilla, an associate professor of biology. The question was, she says: “What are these receptors doing outside the nervous system?”

Her lab’s study, led by graduate student Jessica Houtz and published in the journal Developmental Cell, determined that NGF performs a function in the mature pancreas that has nothing to do with neurons.

Tracing a chain of biochemical signals, the team showed that high blood glucose causes NGF to be released from blood vessels in the pancreas; that NGF signal then prompts pancreatic beta-cells to relax their rigid cytoskeletal structure and release insulin granules into the blood stream.

Using mice as test subjects, the team then used genetic manipulation and drugs to block NGF. They were able to show that the signaling pathway they had found is necessary to increase insulin secretion and glucose tolerance in the mice.

Kuruvilla and colleagues also found that NGF’s ability to increase insulin secretion in response to high glucose also occurs in human beta-cells.

It is not yet clear how this system is affected in people with diabetes.

“We are very interested in knowing whether aspects of this pathway are disrupted in pre-diabetic individuals,” Kuruvilla says. It also would be important to know if NGF or small molecules that bind and activate NGF receptors in the pancreas could be of potential use in the treatment of type 2 diabetes. Future research could explore those questions.

The National Institutes of Health funded the study.