Closer to a Cure for Diabetes?

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.

The National Institutes of Health and Juvenile Diabetes Research Foundation quickly began sponsoring studies of the Edmonton protocol at 10 U.S. centers, and early results from those centers were reported last month at a Miami meeting of the Transplantation Society.

Shapiro’s group reported that 70% of its patients have now been insulin-free for two years and one has been insulin-free for three years. Dr. Bernhard Hering of the University of Minnesota reported that 14 of 16 patients his team had treated were now insulin-free. Ricordi’s team in Miami reported that all nine patients it had treated using the new protocol were insulin-free, and researchers from other NIH-sponsored centers reported similar early results.

But even if the Edmonton protocol “is wildly successful, we could only be helping a couple of thousand people every year” because of the shortage of donor pancreases, Goldstein said.

That’s one reason people were intrigued by the pig cell study reported by Dr. Rafael Valdez of the Children’s Hospital of Mexico. Valdez and colleagues in Canada and New Zealand implanted pig islet cells in 12 diabetics who were 10 to 15 years old. The key to their effort was the simultaneous implantation of Sertoli cells from the pigs.

Sertoli cells, found in the testes, are thought to protect sperm from attack by the immune system by selectively deactivating key immune cells. Many researchers have previously speculated that the cells could provide a similar protection in transplants, and some animal experiments seem to support that.

Valdez told the Miami meeting that one of the recipients was now insulin-free and that half still had functioning grafts--meaning that they required less insulin than before the procedure. He said that the team is now gearing up to expand the study with another 24 patients.

Critics noted, however, that the transplants could not have been performed in the United States because the Food and Drug Administration would not permit them until more animal studies had been performed, especially in primates. Many researchers also fear that such xenograft recipients will become infected with animal viruses--especially the pig endogenous retrovirus, or PERV--which could then be spread to others.

Valdez said that none of the children have shown evidence of such an infection.

Goldstein also questioned why the study had been done in adolescents. “Why not practice it in adults or sicker people?” he said. “Supposing it really is harmful. The children could become sensitized to islets.” If the children later received a transplant of human islets, he said, they could reject them as well.For the long term, researchers are looking at ways to convert stem cells into islets, which offers the potential for yielding unlimited supplies. “In animal experiments, we get something that looks like an islet,” Goldstein said. “If we could do it with human cells, that would be a giant step forward.” But virtually everyone agrees that it will be several years at minimum before researchers can even contemplate human trials of such an approach.