Insulin-Releasing Switch Discovered

Johns Hopkins researchers believe they have uncovered the molecular switch for the secretion of insulin - the hormone that regulates blood sugar - providing for the first time an explanation of this process. In a report published online March 1 in Cell Metabolism, the researchers say the work solves a longtime mystery and may lead to better treatments for type 2 diabetes, the most common form of the disease.

“Before our discovery, the mechanism behind how exactly the insulin-producing beta cells in the islet of Langerhans of the pancreas fail in type 2 diabetes was incompletely understood, making it difficult to design new and better therapies, says Mehboob Hussain, M.D., associate professor of pediatrics, medicine and biological chemistry. “Our research cracks open a decades-long mystery.”

After a meal, the pancreas produces insulin to move glucose from the blood into cells for fuel. People with type 2 diabetes either don’t secrete enough insulin or their cells are resistant to its effects.

In a study designed to figure out more precisely how the pancreas releases insulin, Hussain’s group looked at how other cells in the body release chemicals. One particular protein, Snapin, found in nerve cells, caught their eye because it‘s used by nerve cells to release chemicals necessary for cell communication. Snapin also is found in the insulin-secreting pancreatic beta cells.

To test the role of Snapin, researchers engineered a change to the Snapin gene in mice to keep Snapin permanently “on” in the pancreas. Researchers removed the pancreas cells and grew them in a dish for a day, then added glucose to the cells and took samples to measure how much insulin was released.

When the scientists compared that measurement to what was released by pancreas cells in normal mice, they found that normal mice released about 2.8 billionths of a gram of insulin per cell, whereas the cells from “Snapin-on” mice released 7.3 billionths of a gram of insulin per cell — about three times the normal amount.

“We were surprised to find that the Snapin-on mice didn’t have more or bigger pancreas cells, they just made more insulin naturally,” says Hussain. “This means all our insulin-secreting cells have this amazing reserve of insulin that we didn’t really know existed and a switch that controls it.”

To see if permanently turning off Snapin would reduce insulin release and further demonstrate that Snapin controls the process, the researchers first grew normal mouse pancreas cells in a dish, and treated them with a chemical that stopped them from making the Snapin protein. They again bathed the cells in glucose and measured how much insulin was released by the cells. Normal cells released 5.8 billionths of a gram of insulin, whereas cells with no Snapin only released 1.1 billionths of a gram of insulin — about 80 percent less.

“These results convinced us that Snapin is indeed the switch that releases insulin from the pancreas,” says Hussain.