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Clinical trial shows islet transplantation is a promising procedure

September 28, 2006

The first international, multicenter trial of the Edmonton Protocol-a standardized approach to the transplantation of insulin-producing islets-demonstrates that this may be an appropriate therapy that can dramatically benefit certain patients with severe complications of Type 1 diabetes mellitus.

As described in the September 28, 2006 issue of The New England Journal of Medicine, 36 adult volunteers at nine clinical trial sites in North America and Europe received up to three infusions of islets, which are non-functioning in people with Type 1 diabetes. The trial was designed to gauge how well the transplanted islets would function in regulating blood sugar levels.

Led by James Shapiro, M.D., Ph.D., of the University of Alberta, Edmonton, Canada, and involving an international team of islet transplant researchers, this trial was conducted by the Immune Tolerance Network (ITN). Headquartered at the University of California, San Francisco, the ITN is an international consortium of clinical investigators supported by the National Institute of Allergy and Infectious Diseases (NIAID), the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and the Juvenile Diabetes Research Foundation (JDRF). NIAID and NIDDK are both components of the National Institutes of Health (NIH).

"The results of the trial show the feasibility and reproducibility of islet transplantation using the Edmonton Protocol and has promising implications for the future of treating Type 1 diabetes," says NIH Director Elias A. Zerhouni, M.D.

A year after the final treatment, 44 percent of the transplant recipients no longer needed insulin injections, and an additional 28 percent had partial islet function, which was associated with resolution of hypoglycemic unawareness-a severe complication of diabetes in which people can no longer recognize early symptoms of low blood sugar. Insulin independence did not persist indefinitely in most cases, and less than a third of the people who had been freed from insulin injections after one year remained so by two years. However, individuals with functioning islets had improved control of their diabetes, even though they still needed to take insulin shots. Further research will be needed to improve and prolong the beneficial effects of the procedure, the researchers say.

"Dr. Shapiro and the ITN research team have improved our understanding of the potential of islet transplantation for certain patients with Type 1 diabetes," says NIAID Director Anthony S. Fauci, M.D. "Ongoing studies will further define the clinical utility of this approach."

"This really shows that islet transplantation can be tremendously successful in protecting against hypoglycemic unawareness," says Dr. Shapiro.

About five to ten percent of the estimated 21 million Americans with diabetes have Type 1 diabetes-an autoimmune disease in which the body loses its ability to make insulin due to destruction of islets. Islets are clusters of cells in the pancreas that produce insulin, a hormone the body requires to use glucose (sugar) as a source of energy. This is different from the more common Type 2 diabetes, in which the body produces insulin but has a reduced ability to use it properly. Without insulin, very high levels of glucose accumulate in the blood, causing injury to nerves and blood vessels; at the same time, the glucose is unable to enter cells where the body can use it. Without insulin shots, this condition is fatal. Even with insulin shots, people with Type I diabetes cannot achieve perfectly normal control of their blood sugar. As a result, most people with Type 1 diabetes eventually develop one or more complications, such as heart disease and damage to the eyes, nerves and kidneys.

Healthy individuals and most people with Type 1 diabetes know when their blood sugar is low. Over time, however, some people with Type 1 diabetes develop hypoglycemic unawareness. This condition may make them vulnerable to sudden and severe confusion, fainting and even death if untreated. People with this condition may be unable to perform routine tasks such as driving.

In the last few decades, doctors have been able to treat Type 1 diabetes with pancreas transplantation. The transplanted pancreas senses blood sugar and produces insulin. Many people with diabetes who have taken daily insulin injections for years have achieved total insulin independence after pancreas transplantation-often for years after the transplant. About 1,500 pancreas or pancreas/kidney transplants are performed every year in the United States, and nearly 20,000 of these operations have been performed in the last two decades.

Despite this success, pancreas transplants are not routinely done in patients with Type 1 diabetes because it is a major surgery that carries associated surgical and anesthetic risks. Even without complications, it requires several weeks of recovery at home. In addition, a transplant recipient must stay on immunosuppressive drugs to prevent rejection of the transplanted pancreas. These drugs can have serious side effects, such as kidney damage and vulnerability to infection. For these reasons, pancreas transplantation is almost always reserved for patients who are already undergoing kidney transplantation.

Since the 1970s, doctors have been experimenting with a less invasive procedure, islet transplantation. Islets can be isolated from the pancreas of a deceased donor and then infused into a patient's portal vein, a large vessel that carries blood into the liver. Once in the liver, the islets settle in small blood vessels and begin sensing blood sugar content and producing insulin to control it. This is a safer procedure than a pancreas transplant and can be done in a few hours. Islet transplantation is not as effective as pancreas transplantation, however, in eliminating the need for insulin shots.

In 2000, Dr. Shapiro and his colleagues reported data on seven patients who achieved insulin independence after islet transplantation following a standardized procedure that he designed, which became known as the Edmonton Protocol. The Edmonton Protocol standardizes the procedure for preparing high-quality islets for infusion, testing the function of these islets and transplanting them into the recipient. It also makes use of a regimen of newer immunosuppressants that are less toxic to islets than some older drugs. However, toxicity remains a problem. Some patients in the trial stopped taking their immunosuppressants because of side effects, and as a result, they lost their transplanted islets.

The 36 participants in the clinical trial (mean age 41) had lived with diabetes for an average of 27 years. Each received between one and three infusions of islets. The majority of them had at least partial islet function one year after their final islet infusion, and almost all who did had resolution of hypoglycemic unawareness even if they were not freed from daily insulin injections.

"Even a small number of functioning islets seems sufficient for them to be able to detect low blood sugar and be cured of hypoglycemic unawareness," says Nancy D. Bridges, M.D., chief of the Transplant Immunobiology Branch at NIAID.

NIH/National Institute of Allergy and Infectious Diseases