Clinical Trial Shows Islet Transplantation is
a Promising Procedure For Certain Patients with Severe Type 1
Diabetes
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 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.
The nine clinical sites participating in the trial are: University
of Alberta, Edmonton, Canada; University of Miami; University of
Minnesota; Harvard Medical School; Pacific Northwest Research Institute;
Washington University, St. Louis; Justis-Liebig University, Giessen,
Germany; University of Milan, Italy; and University Hospital of
Geneva.
News releases, fact sheets and other NIAID-related materials
are available on the NIAID Web site at http://www.niaid.nih.gov.
NIAID is a component of the National Institutes of Health. NIAID
supports basic and applied research to prevent, diagnose and treat
infectious diseases such as HIV/AIDS and other sexually transmitted
infections, influenza, tuberculosis, malaria and illness from potential
agents of bioterrorism. NIAID also supports research on basic immunology,
transplantation and immune-related disorders, including autoimmune
diseases, asthma and allergies.
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