Research led by a Johns Hopkins University biologist demonstrates the workings of a biochemical pathway that helps control glucose in the bloodstream, a development that could potentially lead to treatments for diabetes.
In a paper published in the current issue of Developmental Cell, Jessica Houtz, a graduate student working with Rejji Kuruvilla in the Department of Biology at Johns Hopkins, shows that a protein that regulates the development of nerve cells also plays a role in prompting cells in the pancreas to release insulin, a hormone that helps to maintain a normal level of blood sugar. The research on insulin represents a detour for Kuruvilla, whose work has focused on development of the peripheral nervous system. She has studied a group of proteins called neurotrophins, and in particular nerve growth factor [NGF]. These proteins nurture the growth of neurons, the cells of the nervous system.
It has been known for some time that neurons and the pancreatic beta cells, or β-cells, that reside in clusters called islets of Langerhans and produce insulin, have many similarities in molecular makeup and signaling receptors. Receptors are proteins on cell surfaces that respond to particular chemicals and have critical roles in biochemical pathways. Both neurons and pancreatic β-cells have the receptors for neurotrophins.
It turns out that particular nerve growth factor [NGF] performs a function in the mature pancreas that has nothing to do with supporting neurons. Specifically, the research team traced a chain of biochemical signals showing that elevated blood glucose causes particular nerve growth factor to be released from blood vessels in the pancreas, and that the particular nerve growth factor signal then prompts pancreatic β-cells to relax their rigid cytoskeletal structure, releasing insulin granules into the blood stream. Although β-cells also makeparticular nerve growth factor, Kuruvilla and her team found that it was the particular nerve growth factor released from the blood vessels that is needed for insulin secretion.
Using genetic manipulation in mice and drugs to block particular nerve growth factor [NGF] signaling in β-cells, they were able to disrupt distinct elements of this signaling sequence, to show that this classical neuronal pathway is necessary to enhance insulin secretion and glucose tolerance in mice. Importantly, Kuruvilla and colleagues found that particular nerve growth factor’s ability to enhance insulin secretion in response to high glucose also occurs in human β-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 said. It would be of interest to determine if particular nerve growth factor [NGF] or small molecules that bind and activate particular nerve growth factor receptors in the pancreas could be of potential use in the treatment of type-2 diabetes. These are questions to be pursued in further research.
Citation: Houtz, Jessica, Philip Borden, Alexis Ceasrine, Liliana Minichiello, and Rejji Kuruvilla. “Neurotrophin Signaling Is Required for Glucose-Induced Insulin Secretion.” Developmental Cell 39, no. 3 (2016): 329-345.
Research funding: NIH
Adapted from press release by John Hopkins University