Drugs that enhance the activity of calcineurin or NFAT could become a new treatment for type-2

Certain immune-suppressing drugs, such as those taken by patients who have had organ transplants, greatly increase the risk of developing diabetes. These drugs are known to put a stranglehold on a protein called calcineurin.

So it's not exactly a surprise that Seung Kim, MD, PhD, assistant professor of developmental biology at the Stanford University School of Medicine, chose to study why calcineurin inhibition leads to the disease. What is surprising is just how central calcineurin turns out to be in the health and happiness of the insulin-producing pancreatic beta cells. His findings, to be published in the Sept. 21 issue of Nature, could shake up diabetes research, lead to new classes of diabetes drugs and aid in efforts to develop stem cell treatments for diabetes.

"This work has the potential to be big," said Scott Campbell, PhD, vice president of research for the American Diabetes Association. He said that drugs based on this research could potentially expand the numbers of the few beta cells that remain in diabetics and make those cells perform better. "That would have a major impact on the lives of people with diabetes."

In diabetes, the beta cells produce too little insulin or none at all, which prevents cells of the body from being able to take in sugar after a meal. Sugar accumulates in the blood, damaging the blood vessels, kidneys and eyes. Diabetics are also prone to nerve damage. In the United States, 20.8 million people, or 7 percent of the population, have diabetes.

Knowing the potential link between calcineurin-inhibiting drugs and diabetes, Kim and MD/PhD graduate student Jeremy Heit collaborated with Gerald Crabtree, MD, professor of pathology, in a series of experiments to clarify the connection. They worked with mice that had been bred to produce calcineurin in the pancreas only until they were born. After birth, the pancreas in each mouse stopped producing the protein. By 12 weeks of age, the mice, which had been born with a normal number of beta cells, were severely diabetic.

Squelching calcineurin prevented the beta cells from increasing their numbers as the mice grew - more body mass requires more beta cells to keep blood sugar in check. It also reduced the amount of insulin made by the existing beta cells. What's more, calcineurin was found to regulate 10 genes that already had been associated with diabetes.

"This work has led us and others to think in entirely new ways about diabetes," Heit said. Until now people had identified individual genes or processes that were involved in diabetes. The new findings show that these lines of research are connected through a common regulator in calcineurin.

Heit and Kim used further genetic trickery to bypass calcineurin by artificially activating its protein sidekick, called NFAT. Beta cells lacking calcineurin but with active NFAT behaved normally, multiplying as the mice aged and producing normal amounts of insulin.

The implications of these findings are many:

• Drugs that enhance the activity of calcineurin or NFAT could become a new treatment for type-2, or adult-onset diabetes, in which the beta cells don't produce enough insulin.
• Drugs that inhibit calcineurin or NFAT could treat diseases in which the beta cells produce too much insulin, such as hypoglycemia or some pancreatic tumors.
• Treating isolated beta cells with drugs that enhance calcineurin could make those cells divide, producing more cells for transplantation.
• Activating calcineurin could help Kim in his efforts to direct embryonic stem cells to become insulin-producing cells.

Kim, whose work in diabetes includes the development of islet cells, identifying new drug targets and potential stem cell treatments, said the calcineurin findings have wide-ranging implications. "The finding that the calcineurin pathway regulates other pathways in the beta cell makes it highly relevant to many areas of diabetes research," he said.

Campbell said the next step is to verify that the findings in mice also hold true in humans. "This is a step in the right direction and a major leap forward, but now we need to take it into to humans," he said.