Discovery of fly 'pancreas' may lead to diabetes cures

New findings may help scientists develop insulin-producing cells

Fruit flies have cells that function like a miniature pancreas. That’s good news not only for the flies, but also for researchers hoping to use the tiny insects to develop cures for diabetes.

Almost two years ago Seung Kim, MD, PhD, assistant professor of developmental biology and of medicine, and colleagues including then-postdoctoral scholar Eric Rulifson, PhD, found cells in the fruit fly brain that make insulin, one of two sugar-controlling hormones also produced in the human pancreas. Now the scientists have discovered the other crucial half of the pancreatic equation: In research published in the Sept. 16 issue of Nature Kim and Rulifson report finding fruit fly cells that produce a hormone similar to glucagon.

In humans, glucagon and insulin act as a thermostat keeping blood sugar within a normal range. Pancreatic islet cells produce insulin to lower blood sugar after a meal. When the amount of sugar in the blood dips between meals, other pancreatic cells produce glucagon to raise it.

“Without glucagon or insulin you’re in big trouble,” Kim said. “We found that’s also true in flies.”

Kim thinks the two cell types in flies represent a primordial pancreas that scientists can study to better understand how the insulin- and glucagon-producing cells develop and function in humans. An immediate application could be testing new drugs before trying them in more expensive lab animals such as mice.

The flies could also provide insights into how pancreatic islet cells form – information that could help Kim and his colleagues devise ways of coaxing stem cells to develop into pancreatic cells. “We can try to find out what regulates the development of those cells and use that information to help make human islet cells,” he said, adding that stem cells could potentially be used to replace the lost insulin-producing cells in people with diabetes.

About 1 million people in the United States have type-1 diabetes, in which the body’s immune system destroys pancreatic cells that produce insulin. Without insulin, the muscles and liver don’t receive a signal to take up sugar from the blood after a meal. The excess sugar binds to proteins including those that line the blood vessels. If people don’t control their blood sugar using injected insulin, they can develop heart or kidney disease, go blind or require amputations.

Although the insulin- and glucagon-making cells in fruit flies aren’t clumped together in a solid organ such as the human pancreas, they mimic the functions of their human counterpart. Insulin from the fruit fly cells, for instance, signals the insect’s energy-storing organ, called the “fat body,” to store sugar and fat after a meal. When Kim and Rulifson destroyed the insulin-producing cells, causing the equivalent of human diabetes, the fat body no longer received a signal to store sugar, and the fly’s blood sugar skyrocketed. Wiping out the glucagon-producing cells caused the blood sugar to plummet, as in the potentially fatal human condition known as hypoglycemia.

In addition to producing similar molecules, flies and humans have another comparable mechanism for regulating blood sugar, the researchers found. A protein on the insulin-producing and glucagon-producing cells in humans alters its shape when it detects changes in energy levels within the cell. This change triggers the cell to release insulin or glucagon to keep blood sugar and energy levels within a normal range.

Fruit flies have that same protein, but it’s found only on the cell that makes the glucagonlike hormone, called AKH. Kim and Rulifson, now an assistant professor at the University of Pennsylvania, speculate this means that the most ancient hormonal regulators of metabolism first secreted glucagon.

Kim and Rulifson found that the protein, called the sulfonylurea receptor or Sur, regulates the release of AKH, similar to its role in human cells. They found that the protein in flies is so similar to the human protein that it responds to common drugs used by diabetics called sulfonylureas. Prescribed to millions of people with diabetes, these drugs work by helping Sur change shape and allow islet cells to release insulin. These same drugs act on Sur in flies, but the result is a release of AKH rather than insulin.

Kim and Rulifson’s work raises intriguing prospects for future research, said Richard Insel, MD, executive vice president for research at the Juvenile Diabetes Research Foundation in New York. “The fruit fly may serve as a model organism for discovering drugs that affect glucose regulation and hypoglycemia and for better understanding beta cell and islet development,” Insel said.