Implants: a New Shot at Controlling Diabetes : Medicine: A radical procedure called an islet-cell transplant may free some Type 1 diabetics from daily insulin injections.
Mary Arthur celebrated a milestone this year.
She has no pancreas, but Arthur has needed no insulin injections for three years. The reason: a radical new procedure called an islet-cell transplant. It is the longest anyone has survived and remained insulin free with such an implant.
Arthur became diabetic as a 15-year-old high-school sophomore when her pancreas--which secretes life-preserving insulin--was removed along with her liver and stomach during cancer surgery. She immediately received a liver--the only one of those organs she could not live without.
Insulin injections can compensate for the loss of the pancreas, but blood sugar levels can still fluctuate wildly, so Arthur volunteered for a dramatic new procedure at the University of Pittsburgh: Surgeons stripped islet cells from the pancreas of a cadaver and infused them into her liver, where they began functioning just as her own pancreas had.
Arthur is now free to eat whatever she wants and needn’t worry about insulin at all.
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Spurred by such successes and bolstered by President Clinton’s recent lifting of the moratorium on human fetal-cell research, researchers are preparing to launch a major offensive against diabetes. After two decades of frustration in attempts to cure this most common and debilitating disease with transplants of islet cells, surgeons are planning to significantly expand the number of patients who undergo the procedure.
In the long run, they plan to use fetal islets because they should be more readily obtainable, they should proliferate to provide better control of blood-sugar levels and they may be less likely to be rejected. But expanded use of fetal cells will require more research before they can be widely used.
Surgeons hope that islet transplants--whether adult or fetal--will dramatically reduce, or perhaps even eliminate, dependence on insulin shots to control blood-sugar levels. More important, they believe that the transplants will eliminate the wide swings in blood sugar levels that are associated with insulin injections and thereby minimize or eliminate the most severe complications of diabetes, including blindness, kidney disease and nerve damage.
Most of the successes to date have involved transplants of adult islets from cadavers, but researchers have high hopes that fetal islet cells will work even better.
“I think that the groups that have worked in this area will have a new impetus to follow through on the leads that have been stopped” by the moratorium, said Dr. Daniel H. Mintz, a surgeon at the University of Miami School of Medicine. “There will be a resurrection of a lot of work on fetal cell transplants . . . an explosion of new experiences and new information.”
“We’re ready to go back to where we were before the ban,” added Dr. Bent Formby, an endocrinologist at the Sansum Clinic in Santa Barbara, who had successfully transplanted fetal islets into three patients before the moratorium took effect. The lifting of the ban on fetal-cell transplants, he said, “is really a blessing. We are ready to do them again.”
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Type 1 diabetes, or juvenile-onset diabetes, affects more than 1 million Americans and is generally treated with insulin injections. But insulin often does not control the wide swings in blood sugar or the resulting side effects that make diabetes the fifth leading cause of death in the United States.
Researchers have tried smaller, more frequent doses of insulin and mechanical pumps that mimic the action of the pancreas, but the results have been less than perfect.
In addition, pancreas transplants have become common in patients who have had a liver or kidney transplant and are therefore already receiving immunosuppressive drugs. Although the survival rate is improving, pancreas transplants require major surgery and are fraught with complications.
The effort to avoid those problems has focused on attempts to transplant only the islet cells--which account for about 2% of the total bulk of the pancreas. Islets are small clusters of cells within the pancreas that regulate blood sugar concentrations. Beta cells, the most common type of cells within the islets, secrete insulin.
Diabetes results when the body--for reasons not yet clear--attacks and destroys beta cells. Without insulin, the body can no longer properly use and store sugars from food, leading to a rapid buildup of toxins that cause weight loss, irritability, weakness, nausea, coma and ultimately death.
“The major advantage of islet transplantation is that you are only giving the cells that control blood sugar and there are almost no complications associated with it,” said Dr. Charles Brunicardi, a UCLA transplant surgeon. Because surgery is not required to implant islets, “one could imagine getting injections of cells in a clinic and going home the same day.”
Scientists have faced many problems with islet cell transplants, so that the long-term success rate has been low.
Among the 178 transplants that have been performed around the world, the transplanted tissue survived for a full year in only about 20% of the recipients, according to Dr. B. J. Hering, who maintains the International Islet Transplant Registry at the University of Giessen in Germany. The longest surviving implant in a patient with Type 1 diabetes is 2 years and 8 months in a Canadian patient.
Only 10 of the islet recipients are now insulin independent, Hering said. Several others have a reduced need for insulin, however.
Those rather unimpressive results reflect two major problems that researchers have been struggling to overcome.
First, the islet cells have been found to provoke as strong an immune response as does a transplanted pancreas. Second is the disease process that caused the diabetes in the first place. Left unchecked, the autoimmune process that destroyed the islets before will also destroy the transplanted islets.
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Researchers are making progress on both fronts. Scientists have largely resolved the immune/rejection problem through a number of techniques:
* Biologist Kevin J. Lafferty of the University of Colorado Health Sciences Center in Denver has found that immunogenicity can be greatly reduced by growing the islet cells in a laboratory dish in the presence of high concentrations of oxygen.
* Irradiating them with ultraviolet light also reduces immunogenicity.
* New anti-rejection drugs have also proved helpful. Many islet recipients have done well with a relatively new drug called FK-506, and Sutherland has had even better results with a still newer drug called deoxyspergualin.
Among those tackling the autoimmune problem, the most promising results have been obtained by Miami’s Mintz.
He has three patients in whom the islet transplants have survived for three years and whose blood sugar levels “are absolutely normal”--hinting that those patients may avoid some of the complications of diabetes. They receive about 20% of the insulin they required before their transplants, even though two could be insulin independent, Mintz said.
“It’s our choice to keep them on the insulin because we believe it protects the graft,” Mintz said. The same principle is now being used in some clinical trials in which researchers are trying to prevent the onset of diabetes. Mintz believes that administration of small amounts of insulin prevents the appearance of proteins on the islets’ surface that cause the immune system to attack.
The Miami group will transplant 12 to 18 new patients this year, more than two years after they did their first six procedures. (Three patients rejected the islets.) They had stopped performing transplants while they waited for evidence that the grafts would survive.
Other groups are also planning to expand the number of transplants. But for the longer term, many researchers are putting their hope in fetal islet cells.
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Fetuses “are potentially a great source of tissue once we have worked out some of the problems with adult transplants,” said Dr. Camillo Ricordi, a transplant surgeon at Pitt.
To date, 221 fetal islet grafts have occurred worldwide, according to Hering, the vast majority of them outside the United States. Russian and Chinese scientists have reported great success with the procedure, but Western researchers hesitate to accept those reports at face value because they have not appeared in peer-reviewed medical journals.
Western researchers have had less success with fetal cell transplants, primarily because of the same problems that have afflicted grafts with cadaveric islets. But most of those efforts, particularly in the United States, occurred before the moratorium and did not incorporate any of techniques recently developed to prolong transplant life. Researchers thus hope that new efforts will reflect the successes obtained with adult islets.
The lifting of the moratorium will certainly accelerate research on fetal islets, most agree. UCLA’s Brunicardi and Mullen, who transplanted cadaveric islets into three patients last year, will give a combination of adult and fetal islets to five patients this year. They hope that the adult islets will provide immediate benefits, while the fetal islets will provide long-term control. Others, like Santa Barbara’s Formby, will use fetal islets alone.
But it may take time for others to gear up for fetal cell transplants, according to Dr. Alberto Hayek, a pediatric endocrinologist at the Wittier Institute for Diabetes and Endocrinology in La Jolla. He has been trying for a year to put together a team to study fetal cell transplants, but “It was very difficult . . . not knowing who was going to win the election.”
His new team could begin transplants within a year, he added, “but it all depends on the availability of tissue.”
Hayek hopes that the National Institutes of Health or some other organization will establish a mechanism for providing aborted tissues to researchers who need them.
For the moment, however, many researchers will continue to use adult islets. “It may be easier to work out the problems with islet transplants with adult tissue because it (the graft) works immediately, whereas with fetal tissue you may have to wait for months . . . to see the functional result of your procedure,” Ricordi said.
Mary Arthur, meanwhile, has been doubly blessed. Five other pancreas-cancer patients have received similarly successful islet-cell transplants at Pitt only to die from a recurrence of their cancer. Hers is still in remission. Despite missing a year of school, she graduated with the rest of her class and now, at age 18, is attending culinary school in her hometown of Louisville.
“I’m very glad I had it (the transplant),” she says. “I’d have no hesitation about recommending it to anyone else.”
