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Closer to a Cure for Diabetes?

Research* Transplants of insulin-secreting cells show promise. But even if the technique catches on, donor cells are hard to come by.


Daily insulin injections are lifesaving for diabetics, but to many people they rep-resent a heavy burden that can interfere with their professional and social lives. The wide swings in blood sugar levels that can occur when injections are given only once or twice a day, furthermore, are now known to be the cause of virtually all the complications of diabetes, ranging from nerve damage to heart disease to blindness.

But the hunt for a cure--rather than just an ongoing treatment--has yielded few results. Pancreas transplants are such a cure, but surgeons are reluctant to perform them because of side effects from the powerful drugs required.

For at least two decades, scientists have believed that transplanting only insulin-secreting islet cells from the pancreas might present a better alternative, but it proved difficult to keep the transplants alive and functioning and only a few diabetics have benefited.

Then, three years ago, researchers developed a new technique called the Edmonton protocol that has revolutionized islet cell transplants, promising to bring a cure to much larger numbers of patients with Type 1 diabetes.

Only about 200 patients have been treated so far using the protocol, but the results have been remarkable. Three-quarters of patients who have received the transplants have remained insulin-free--not requiring injections of the hormone--for at least a year, according to researchers, a dramatic increase from the 10% to 15% success rates reported before the development of the technique.

"We're definitely past the proof-of-concept stage," said Dr. Craig Smith of the UCLA Medical Center. "Now we need to take the field forward and make it more applicable to a wider population."

But one of the key problems impeding the transplants is the lack of sufficient donor pancreases, which are the source of the islet cells. Only about 6,000 donor pancreases are available each year, according to Dr. Robert Goldstein, chief scientific officer for the Juvenile Diabetes Research Foundation, while as many as 1 million Americans with Type 1 diabetes could potentially benefit from the surgery.

People with Type 2, or adult-onset, diabetes are unlikely to benefit. Most with this form of the disease continue to make insulin, but their cells become resistant to its effects for reasons that are not clear. Instead, they use drugs that stimulate the production of more insulin or make their bodies more sensitive to insulin.

Researchers are thus looking at alternative sources for islet cells, such as growing them in culture, producing them from stem cells, or even using islets from other species. Most of these approaches are still far from use in humans, but Mexican and Canadian researchers startled fellow scientists recently by revealing that they had successfully implanted pig islets in adolescent diabetics--without using immune-suppressing drugs.

If the research can be replicated, "it's truly the most remarkable result ever following an islet transplant experiment," said Dr. Camillo Ricordi of the University of Miami. But, he added, the scientific community will remain very skeptical "until more data is available and more patients are studied."

Islet cells make up only about 1% of the pancreas. Type 1 diabetes results when the islets are destroyed by an autoimmune reaction for reasons that scientists do not yet understand. Although insulin pumps can deliver a steady dose of the hormone, these devices are relatively new and most patients still rely on injections of insulin to control their disease.

The "gold standard" for curing diabetes is a pancreas transplant, which is successful in about 80% of cases. Only about 1,200 such transplants are performed every year worldwide, however, because the pancreas produces a strong immune response in the recipient and powerful immunosuppressive drugs must be used to prevent rejection. Most doctors do not think the benefits outweigh the risk associated with the drugs.

Surgeons thus transplant a pancreas only when a patient is also receiving a kidney transplant, and thus has to take the drugs anyway.

Islet cells alone do not trigger such a powerful rejection reaction, and researchers had hoped they would be easier to work with than an intact pancreas. That did not prove to be the case, however, until 1999. In that year, Dr. James Shapiro of the University of Alberta reported that the first eight patients his group treated using a new protocol remained insulin-free for at least a year.

The key to his success was the use of a new combination of anti-rejection drugs--sirolimus, tacrolimus and daclizumab.

Shapiro's team used a combination of enzymes to remove the islet cells from two donor pancreases for each recipient. After the islets were purified, they were immediately infused into the portal vein leading into the liver, where the cells took up residence, began producing insulin and releasing it into the bloodstream.

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