A Seminar for Solutions - Searching for Future Treatments
I was among the 400 individuals who attended Today's Solutions for Type 1 Diabetes in St. Louis this past May. The seminar, organized and hosted by the Insulin-Free World Foundation, brought together leading researchers and those of us living with the disease to discuss current transplant options and possible future treatments.
Among the issues raised during the seminar was how the benefits and risks of pancreas vs. islet transplantation compared. Specifically, is it better to undergo a pancreas transplant today and submit to lifelong immunosuppressive-drug treatment or hold out for the promise of an islet transplant and an array of potential new methods that may have few, if any, side effects.
This issue, and the data presented at the seminar, were all too familiar to me. Having had diabetes for 38 years, and having worked at the Diabetes Research Institute (DRI) in Miami for nearly 25 of them, I have been able to keep abreast of the progress and challenges of emerging diabetes treatments. I also have personal experience with transplantation and immunosuppression, having received a kidney transplant nearly 17 years ago. Because the kidney was a good match - my mother was the donor - it allowed me to use relatively low doses of immunosuppressive drugs. Nevertheless, years of diabetes and medications have begun to take their toll, and sometime in the very near future I will be facing another transplant. Fortunately, as discussed during the seminar, more options are available today than at the time of my transplant.
Success in Islet Research
Among the presenters at the conference was the Diabetes Institute for Immunology and Transplantation's Dr. Bernhard Hering, director of the islet transplant program at the University of Minnesota. Dr. Hering gave attendees a comprehensive overview of islet transplantation. He noted that in the 1970s and 1980s a major focus of islet research was to increase the numbers of islets isolated from each pancreas. During those years, fewer than 250 islet transplants were performed, with only a few cases achieving long-term islet function. Most, if not all, of these patients received islet cells from multiple donors due to the limitations of islet isolation technology.
Dr. Hering credited Dr. Camillo Ricordi, now scientific director of the DRI in Miami, as having made the next major advance in the field of islet transplantation. Dr. Ricordi's automated islet isolation methodology enabled researchers to obtain enough islets from a single pancreas to treat a recipient. His system, or variations thereof, are now in use worldwide.
A number of seminar attendees were living testaments to the results of this cumulative research. These included Arkansas resident Don Smith, who underwent a simultaneous kidney-islet transplant five years ago. The islet transplant was performed at Washington University in St. Louis by Dr. David Scharp a pioneer of islet transplantation techniques, who had worked in conjunction with Dr. Paul Lacy. Since that procedure, Don has remained free from injected insulin.
Dr. Hering also presented recent data from Washington University, the University of Minnesota, The University of Miami and the University of Giessen in Germany, which showed the success rate of islet transplants to be steadily improving. He specially cited a recent article in Diabetes by Drs. Rodolfo Alejandro, Daniel Mintz, and their colleagues at the DRI, which reported success in long-term islet function in type 1 patients who previously had received a kidney transplant.
Collectively, the multicenter studies have shown that islets can be isolated and infused non-surgically, successfully take up residence in the liver, develop their own blood supply and continue to function for more than seven years. While insulin independence is clearly the goal of islet transplantation, patients who have received islets and maintained only partial function, requiring small doses of insulin, continue to have normal HbA1cs and have eliminated the occurrence of severe hypoglycemia.
Dr. Hering also cited a recent presentation at the American Society for Transplant Surgeons in Chicago by Dr. Norma S. Kenyon, director of preclinical research and associate director of cell transplantation at the DRI. Dr. Kenyon demonstrated that a new drug (anti CD154) given in combination with islets, resulted in normal blood sugars for as long as 300 days in several primate species. Her results showed that the treated animals' islet function mimicked that of healthy animals.
Dr. Hering indicated that this work could have great clinical significance and represents one of many new therapies that can take islet transplantation to the next level. He also envisioned a day when a patient could visit his or her doctor's office and be freed from having to inject insulin with a single treatment.
Of course, a reliable and sufficient source of these insulin-producing cells will be needed to make such a future a reality. While the use of pig islets and genetically engineered cells are possible options, another approach may be to "grow" human islets. Dr. Alberto Hayek, professor of pediatrics and director of the islet research laboratory at the University of California, San Diego, and chairman of the Whittier Institute for Diabetes and Endocrinology, addressed this topic.
Dr. Hayek's group has demonstrated that both adult and fetal islets can be made to proliferate in the laboratory. Challenges remain in obtaining normal insulin function in these expanded cells. These challenges, however, may one day be resolved through the use of growth factors in combination with gene therapy. Dr. Hayek's laboratory research also involves testing various sites for islet transplantation, including the pancreas.
Pancreas Transplants Today
Dr. David Sutherland, director of the Institute for Immunology and Transplantation and head of transplantation at the University of Minnesota, gave a rapid-fire, statistically-packed presentation on pancreas transplants. A pioneer in this field, Dr. Sutherland described the increasing success of this procedure, particularly in the last few years. To offer some perspective, when I had my kidney transplant in 1982, the mortality and morbidity of pancreas transplantation was over 50 percent. Improvements in surgical technique and, more recently, the availability of new drugs, have dramatically improved these numbers. Dr. Sutherland reported that only about 10 to 20 percent of the patients receiving pancreas transplants today are required to undergo corrective surgical procedures.
Dr. Sutherland also reported on his increasing number of clinical experiences with pancreas-only transplants in patients with hypoglycemic unawareness and in those whose best efforts to control their diabetes have failed. He cited surveys that indicate an improved quality of life not only for the individual, but for the entire family.
Listening to Dr. Sutherland's presentation was Deborah Butterfield, executive director of the Insulin-Free World Foundation. Ms. Butterfield's second attempt at a kidney-pancreas transplant greatly improved her quality of life and has kept her free from insulin injections for the last several years. This success followed a previously attempted pancreas transplant that failed after months of hospitalization.
Clearly, pancreas transplantation has become a viable option. The only questions are: when and for whom?
Dr. Sutherland recommended that a patient undergo pancreas transplantation before complications from the disease develop. The current practice is to wait for complications to appear and then perform a kidney-pancreas transplant or pancreas-after-kidney transplant. He suggested that the risks of life-long immunosuppression may be a better alternative than those associated with long-term diabetes. The problem, of course, is that no one knows who will develop serious complications from diabetes, or when.
Making the Decision
All of us with type 1 diabetes must carefully weigh our treatment options with our physicians and families. The decision is always difficult and fraught with uncertainties. I have personally seen the harm diabetes and immunosuppression can cause. Since my kidney transplant in 1982, I have broken bones in my feet seven times, had a cataract removed from my one useful eye, had two cancerous skin lesions removed and acquired hepatitis C, which eliminated the possibility of infusing islets into my liver. These are only some of the potential side effects of long-term immunosuppressive therapy.
But the horizon is becoming brighter. Emerging technologies such as encapsulation, specifically targeted antibodies, and the use of bone marrow components are rapidly expanding transplant options and improving outcomes.
As I consider my next kidney transplant, I may opt for a simultaneous kidney-pancreas transplant. Alternatively, if a good living-related kidney is available, I may opt for the kidney first and have the pancreas transplant six months to a year later. In the intervening time, new therapies may become available. After all, when I received my first kidney, such transplants were controversial, and I was told that the average graft survival was five years. We have come a long way.
Gary Kleiman is the executive director of medical development at the University of Miami's Diabetes Research Institute, where he helps lead the organization's national fundraising and public affairs activities.
More information on the seminar is available at www.insulin-free.org/conference. To obtain transcripts or audiocassettes of the seminar, contact the Insulin-Free World Foundation at: Insulin-Free World Foundation; 750 S. Hanley Road, Suite 360; St. Louis, MO 63105. Phone: (888) RING-IFW or (314) 727-4247.
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