New approach counters diabetes in mice trials

SAN FRANCISCO CHRONICLE

Thursday, December 11, 2008

Matthew Kalman, Chronicle Foreign Service

Beersheba, Israel -- When he was just 7 years old, Sacramento native Nate DeFelice was told he had Type 1 diabetes. So when he joined a diabetes research project at Ben-Gurion University here two years ago, he hoped it would be a meaningful experience.

As it turns out, the project could change his life and those of millions of other diabetics.

DeFelice, 27, never dreamed that he would help discover a potential cure for his disease, see the beginning of a Federal Drug Administration-approved clinical trial in the United States and co-author a scientific paper along with seven other researchers published in October by the National Academy of Sciences.

"It's exciting," said DeFelice, who studies pediatric medicine at the university's international health program run and must inject himself with insulin six times a day and check his blood sugar levels 10 times a day. "Managing diabetes is a full-time job."

Type 1 diabetes, usually diagnosed in childhood, is caused by a failure of the insulin-producing cells in the pancreas called "islets." They require daily injections of insulin, which helps break down glucose in the blood. As glucose levels rise, diabetics can suffer blindness and even death.

In Type 2 diabetes, sufferers cannot use insulin effectively but can sometimes manage their condition with lifestyle changes. Oral drugs, however, are often required - and less frequently insulin - to achieve metabolic control. Most people with diabetes have Type 2.

Welcome opportunity

When Ben-Gurion University biochemistry Professor Dr. Eli Lewis asked for volunteers to participate in new research on diabetes, DeFelice jumped at the chance.

Diabetes "is something I'm constantly aware of and constantly taking care of," said DeFelice. "It's a part of me, but I'd be happy to get rid of it."

Lewis, DeFelice and the other researchers have focused their investigations on islet transplantation. In 2000, doctors at more than 50 research sites in the United States, Canada, Europe and Japan transplanted healthy islets into diabetes patients, hoping the newly grafted cells would secrete insulin and effectively cure the disease.

But the cells were rejected, and patients resumed insulin injections after a few months.

The Israeli team then opted for a new approach, ignoring the rejection of the grafted cells and focusing instead on inflammation caused by the transplant itself. Lewis grafted healthy islets into diabetic mice and treated them with an anti-inflammatory drug called alpha-1-antitrypsin, or AAT. Within months, they discovered three encouraging results:

-- AAT enabled the newly grafted islets to survive indefinitely, successfully secreting insulin to control glucose levels like healthy pancreas cells.

-- The researchers stopped administering AAT and the islets continued to function. "We withdrew the therapy. That is something that is unique in transplant today," Lewis explained. "There is no approach today that is able to provide a limited amount of therapy. If a patient stops the current protocol therapy, any graft will be rejected: kidney, heart, lungs - including islets."

-- The third result surprised even the scientists. They found that even after transplant and halting therapies, the mice's immune systems remained intact and were able to reject additional grafts while the original transplant continued to function. Doctors call this state "tolerance," which means the immune system remains intact and able to attack foreign bodies while protecting the inserted graft.

"We were able to cure a mouse from diabetes by supplying the healthy cells and the mouse's immune system still functioned," Lewis said. "This is the closest thing that we can consider to cure diabetes."

If healthy islets that secrete insulin and control the body's glucose levels can be successfully transplanted, diabetics would be cured of diabetes, Lewis said. By using AAT, the researchers cured diabetes in mice and are hopeful they can do the same for humans. It is not yet clear what the transplant procedure would mean for sufferers of Type 2 diabetes.

'Impressive' results

The Israeli team's findings have caused much excitement among medical experts.

"The results of this study are really impressive," said Marc Donath of the Clinic of Endocrinology and Diabetes at the University Hospital in Zurich. "This study is a realistic hope not only for islet transplantation, but also for other organ transplantation."

Thomas Mandrup-Poulsen, chief physician of the Steno Diabetes Center and Faculty of Health Sciences at the University of Copenhagen, says the Israeli team is "at the frontier of islet research."

In the next year or so, the Israeli team will work with colleagues at Harvard University and other U.S. centers in FDA-approved clinical trials.

"Our study is ongoing," said Lewis.

Meanwhile, DeFelice says he prefers to wait for the results before breaking out the bubbly.

"Mice models are very different to human models," said DeFelice. "It's a black box."

This article appeared on page A - 14 of the San Francisco Chronicle