Transplanted Hopes.

Islet-cell success may bring a diabetes cure closer

A compelling description of untreated diabetes comes from Aretaeus of Cappadocia. Writing in the second century A.D., he called the disease "a melting down of the flesh and limbs to urine."

Despite such an early recognition of the symptoms and severity of diabetes, effective treatment proved elusive. In the late 1800s, researchers localized the problem to the pancreas, a 100-gram digestive-system organ located just behind the stomach, and they figured out that people with the disease don't process sugar effectively.

In 1921, Canadian researchers isolated insulin from dog pancreases and discovered that the hormone is essential to controlling blood sugar. Given by injection, insulin reversed wasting in diabetic children and extended their lives.

Dramatic as its effects are, however, insulin isn't a cure for diabetes. People with the disorder must monitor their blood sugar closely and take insulin injections to reduce the risk of nerve damage and heart, kidney, and eye disease. In a small percentage of these people, insulin injections fail to keep blood-sugar concentrations from fluctuating wildly.

Scientists and patients agree that the ideal diabetes treatment would control patients' blood-sugar concentrations without requiring them to take insulin. One long-sought option is transplantation of pancreatic cell clusters, called islets, that make insulin. Though the approach is simple, it has succeeded in only a small fraction of the attempts.

This year, however, a Canadian team announced 11 consecutive successes--islet transplants that permitted the recipients to stop taking insulin. Although there are still questions about the long-term safety and efficacy of this treatment, there's a sense of excitement among researchers. In Toronto at the June meeting of the Endocrine Society, David M. Harlan of the National Institutes of Health in Bethesda noted, "Islet-cell transplantation, which has long been promising, appears poised to fulfill its promise."

Affecting 1 million people in the United States, type I diabetes arises when a patient's immune system attacks the insulin-producing cells in the pancreas. While a pancreas transplant effectively cures the diabetes in most cases, the procedure is difficult and expensive and few donor pancreases are available.

Physicians can transplant just the insulin-producing cells in a less taxing process that doesn't require major surgery. For the past 25 years, they've tested procedures in which they inject the cells into the major blood vessel flowing to the liver. The cells can take up residence there. After the procedure, patients must take immunosuppressive drugs. Overall, just 8 percent of people given islet-cell transplants have improved their ability to control blood-sugar concentration enough to stop taking insulin.

In the recent work, all 11 patients receiving islet cells had had poorly controlled type I diabetes. "We convert the entire pancreas into something that is less than the size of a teaspoon," says, A.M. James Shapiro who headed the study at the University of Edmonton in Alberta. "It is the easiest transplant in the world."

Shapiro's team injected about 12,000 islets per kilogram of a person's body weight. The islets were isolated from two to three donor pancreases. The scientists followed the patients for as long as 15 months. Since being treated in the Edmonton experiment, no patient has needed to take insulin shots, says Shapiro.

He and his colleagues suspected that widely used immune-suppressing drugs, such as glucocorticoids, damage islets, so they replaced them with newer drugs that they thought wouldn't damage the islets. These include sirolimus, tacrolimus, and daclizumab.

The researchers also reduced the time it takes to isolate and purify the insulin-producing cells from the donor pancreases and begin the transplantation surgery.

Since the transplants, the patients' blood-sugar concentrations have been in the normal range, although some patients have shown slight difficulties in controlling high concentrations of blood sugar, Shapiro says.

The team reported on their first seven patients in the July 27 NEW ENGLAND JOURNAL OF MEDICINE and updated their results at the American Diabetes Association meeting in San Antonio in June.

"This is a very important initial step," says Aldo A. Rossini of the University of Massachusetts Medical School in Worcester. "They are demonstrating for the very first time that if we are able to provide enough islet cells, we are able to quote-unquote cure the disease."

The Juvenile Diabetes Foundation International in New York and NIH have joined forces to sponsor more clinical trials of the Edmonton transplant procedures. Worldwide, about 40 adults with diabetes will receive islet transplants over the next 18 months, says Richard W. Furlanetto of the foundation.

In the long run, if the transplants work for people with type I diabetes, researchers may also try them as a way of controlling type II diabetes, says Paul Robertson of the Pacific Northwest Research Institute in Seattle. Type II diabetes, which affects 15 million people in the United States, is caused by an inability to respond to insulin. Many people with type II diabetes become dependent on insulin injections.

"Advances in islet-cell transplantation have been a long time in coming, so it is easy to get excited," cautions Chris Saudek of Johns Hopkins University School of Medicine in Baltimore and vice president of the American Diabetes Association. The Edmonton study "is a large step, really the first time that someone has shown [islet transplants] can work reliably," he says. "But for patients to draw the conclusion that they will be transplanted in the very near future is another very large step."

"There are still breakthroughs that need to be made" before islet transplants become widespread, Saudek says.

Several major questions face the researchers. The first is, How long will the transplanted cells survive and provide adequate insulin?

There's a good chance that islet transplants will function over the long term, says Robertson. He's followed six people who had their own islet cells implanted in their livers after surgeons removed the patients' pancreases for reasons unrelated to islet function. Without such an implant, its pancreas removal leads to diabetes.

At the American Diabetes Association meeting, Robertson reported that over the 10 to 13 years that he's periodically examined the patients, none have developed diabetes. So, the transplanted islet cells must continue to function.

Even if islet transplants don't last for a person's lifetime, he says, their failure isn't a death sentence. People can always go back on insulin injections.

A second question is whether people who receive transplants must stay on immunosuppressive drugs for the rest of their lives. Such drugs make people prone to serious infections and can increase their chances of developing cancer.

Researchers are looking for treatments that prevent attacks on the transplanted cells without suppressing the entire immune system. Until recently, the most promising experimental therapy was an antibody against CD-40, one of the proteins expressed on the surface of some immune cells, says Furlanetto. Norma Kenyon of the University of Miami School of Medicine has shown that in mice, and sometimes in rhesus monkeys, this antibody can prevent rejection of islet transplants.

Last year, however, the company making the antibody pulled it out of clinical trials in which researchers were testing its effects as a treatment for autoimmune diseases, Kenyon says. Participants receiving the antibody were more likely to develop blood clots in their limbs, hearts, or brains than were those receiving a placebo. The company that makes the antibody reports being "cautiously optimistic" that scientists can tweak the drug's structure to reduce side effects, Rossini says.

Another approach for inducing the immune system to tolerate foreign tissue is to give a patient a transplant of bone marrow cells along with the islet cells. This difficult and expensive procedure, which requires destruction of the patient's own bone marrow, has already shown some success in transplants of liver and heart (SN: 5/22/99, p. 331). However, Rossini says, "I don't feel we can justify bone marrow transplants for diabetes," a disease that is not immediately fatal and can be treated by other means.

If researchers solve the critical issue of immune suppression, they'll need to increase the supply of islet cells. Only about 3,000 healthy pancreases become available to transplant each year in the United States. The pancreas quickly suffers damage after death, as its digestive juices eat away the organ.

An intact human pancreas contains about a million islets, each made of four cell types. In the Edmonton experiments, each adult pancreas yielded between 400,000 and 600,000 islets, not enough for a successful transplant. About 80 percent of the cells in these islets are the beta cells, which produce insulin.

Theoretically, many fewer beta cells than are currently transplanted will produce enough insulin to regulate blood-sugar concentrations, Shapiro says. Researchers don't know why many of the islet cells don't thrive after the transplant.

Instead of isolating human islet cells, some researchers have suggested transplanting pig cells (SN: 11/4/95, p. 298). Pig islets--which produce insulin that's almost identical to human insulin--can be genetically engineered to express human proteins. To further reduce the risk of a person's immune system rejecting the islets as foreign, physicians might transplant pig islets enclosed in a capsule that permits insulin to seep out but blocks immune cells from attacking the foreign tissue.

"Although pig islets work beautifully in rodents, there are many hurdles before they can be used safely in humans," notes Susan Bonner-Weir of Harvard University's Joslin Diabetes Center in Boston.

Other researchers are attempting to produce large quantities of insulin-producing cells in the laboratory. Normal human beta cells can grow in test tubes, but not indefinitely. Cultures of beta cells that have been manipulated to keep growing usually don't produce insulin. To get a steady supply of cells suitable for transplant, Fred Levine of the University of California, San Diego Cancer Center added genes that encourage unlimited cell growth and others that permit insulin production.

Diabetic mice given the cells have survived without extra insulin, Levine reported at the June diabetes meeting.

Before such cells can be transplanted into people, Levine and his colleagues will need to perform a complicated step to remove the genes that enable the beta cells to grow rapidly in culture. Even if the genes were turned off when transplanted, there's concern that they would later become activated and cause cancer.

"Unless you can get the gene [that enables unrestricted cell growth] out of absolutely every cell," warns Furlanetto, "there's a possibility of developing insulinoma," a nonmalignant islet tumor that can cause dangerously low blood sugar.

Laboratory production of isolated beta cells raises another question: Are these cells as effective as entire islets in controlling diabetes and limiting its side effects? The nonbeta cells in human islets also produce proteins--such as glucogon or C-reactive protein--that may play some role in preventing diabetes-related complications, says Bonner-Weir.

Therefore, she and her colleagues are trying to culture whole islets. The Boston researchers retrieve duct cells from human pancreatic tissue usually discarded after scientists have extracted islets for transplantation. They've coaxed these cells to become less specialized and then develop into isletlike structures that churn out insulin.

Over the course of a month, these clusters increased their insulin production by 10 to 15 fold, Bonner-Weir and her colleagues report in the July 5 PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES. They estimate that the procedure would have generated only about 32,000 new islet cells if they had cultured all the duct cells from a pancreas, still far too few for an islet transplant for a single patient.

"The initial experiments are very promising," says Furlanetto, "but we need a significantly better yield to make it a viable method" of obtaining islets.

Researchers haven't yet demonstrated the effectiveness of laboratory-grown cells at maintaining a patient's blood sugar concentration. It's crucial that these cells produce more insulin when exposed to higher concentrations of sugar in the blood, as normal islet cells do.

Bonner-Weir says that the islets she and her team have grown produce more insulin in response to higher concentrations of glucose and very little or none at the concentrations of blood sugar found in the blood of a person who hasn't eaten recently.

For the present, the risks and limitations of islet-transplant procedures require that the vast majority of patients will have to be satisfied with taking insulin, Furlanetto cautions.

The success of the Canadian procedure gives researchers a benchmark to use in measuring the effectiveness of lab-grown islets. It also opens the way for testing different regimens for inducing a person's immune system to tolerate the transplanted islets.

"We could, in the next 5 years, see some really dramatic changes in what we do for diabetic patients," especially those who are most severely ill, Furlanetto says. "Islet transplantation is a fact. It can be done. Now, you just need to perfect it," he says. "That's what the excitement is. This is not a pie-in-the-sky idea any longer."