Can Islet-Cell Transplants Gain New Life?
Mentor Michael McDaniel (right) and postdoctoral fellow Nidhi Rohatgi.
Michael McDaniel, PhD
Professor of Pathology and Immunology, Washington University School of Medicine in St. Louis
|ADA Research Funding|
Mentor-Based Postdoctoral Fellowship
The islets of Langerhans sound like exotic, far-off vacation destinations. But they're not an island chain in the Caribbean. For people with diabetes, these strangely named structures couldn't be closer to home: The islets of Langerhans are tiny clusters of hormone-producing cells. There are about a million of them in the pancreas, an organ the size of a hot dog that's nestled deep in your gut.
Since German anatomist Paul Langerhans identified them way back in 1869, scientists have learned a lot about the islets. Doctors now know, for example, that beta cells in the islets of Langerhans are responsible for producing insulin, a hormone that tells the body to absorb glucose from the bloodstream. (They also produce a handful of other critical hormones, including glucagon and ghrelin.)
Researchers also know that when these cells are attacked by the immune system or wear out from overuse, the results are dire. Without the insulin that beta cells produce, glucose builds up in the bloodstream to levels that damage organs, blood vessels, and nerves. That's diabetes, a condition affecting nearly 26 million people in the United States alone.
In the past 15 years, researchers began to wonder whether dead or worn-out islets could be replaced by transplanted islets from a cadaver donor, just as hearts, livers, and other organs are. In 2000, a group of researchers in Canada transplanted islet cells from a cadaver into people with type 1 diabetes. The operation seemed to cure type 1 diabetes—at first. "They were very successful in treating human patients with type 1," says Washington University in St. Louis researcher Michael McDaniel. "In the first year, patients were off exogenous [external] insulin."
But the cure didn't last. Over time, the transplanted islets stopped working: Within two years of the transplants, most of the patients in the study had to inject insulin again. Researchers examining the cells in the lab found that something about the process of transplantation was making the beta cells less effective.
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One problem is the need for heavy doses of anti-rejection drugs—which prevent the immune system from attacking the transplanted beta cells but result in serious side effects, including a weakened immune system, high LDL ("bad") cholesterol, fatigue, and anemia. One of the drugs, rapamycin, even prevents the islet cells from duplicating.
And each transplant patient requires from two to four donor pancreases to normalize blood glucose levels. The long list of drawbacks to the procedure made doctors and patients wonder whether the trade-off was worth it.
New research may change the equation. "We're trying to find ways to culture human donor islets to increase the number of insulin-secreting beta cells so that only one pancreas may be required for transplantation," says Nidhi Rohatgi, PhD, a postdoctoral fellow working with McDaniel. With a grant from the American Diabetes Association, McDaniel, Rohatgi, and a team of researchers at Washington University are working on ways to pep up beta cells before and after transplantation, a crucial first step in making islet transplants widely feasible.
They've lit on new potential for a drug class that was once touted as a magic bullet for type 2 diabetes. Called thiazolidinedione (or TZD) drugs when they were discovered in the 1980s, these medications were prescribed for years under trade names such as Rezulin, Avandia, and Actos. "It was a pill to correct blood glucose levels by making insulin work better—a clear breakthrough," McDaniel says.
But the way TZDs worked has not been understood until now. Patients taking them began having serious side effects, from weight gain to liver failure and cardiovascular disease. Rezulin (troglitazone) was taken off the market, Avandia (rosiglitazone) is now prescribed subject to significant restrictions, and Actos (pioglitazone) carries a Food and Drug Administration warning that its prolonged use may be associated with an increased risk of bladder cancer.
New discoveries, however, have changed the way researchers understand the drugs' impact on the body. This has led to the development of a new class of TZDs called mTOT modulators. McDaniel and Rohatgi hope this better understanding can open up new possibilities in treating diabetes. Their lab is focusing on a prototype mTOT modulator that they say has the good effects of the old TZDs without triggering the bad side effects. So far, the drug has dramatically improved the culture of beta cells in petri dishes. "Our data show mTOT modulators have a very strong effect on survival and function of human islets," Rohatgi says.
The next step is to transplant the mTOT modulator–treated human islets into lab animals to see what happens. "We hope to see that these treated human islets will allow us to decrease blood glucose levels in mice using fewer islets that will remain functional for a longer time," Rohatgi says. If the results live up to their hopes, it might mean there are ways to make transplanted islets of Langerhans last a lifetime.