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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 o
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Contact: Amy Adams
amyadams@stanford.edu
650-723-3900
Stanford University Medical Center
20-Sep-2006