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Transplanted Pig Islet Cells Keep Diabetic Baboon Off Insulin

Transplanted Pig Islet Cells Keep Diabetic Baboon Off Insulin
Transplanted Pig Islet Cells Keep Diabetic Baboon Off Insulin


Duke Health News Duke Health News

INNSBRUCK, Austria – Duke University Medical Center
researchers reported Friday that specially encapsulated
insulin-producing pancreas cells from pigs have kept a diabetic
baboon from needing insulin for more than nine months. If this
approach continues to show success in similar experimental
models, the researchers believe that trials involving humans
with insulin-dependant diabetes could begin within a year.

The researchers coated islet cells taken from pig pancreases
with a complex carbohydrate known as alginate and injected the
resulting spheres into the abdominal cavity of a diabetic
baboon. The cells reacted properly to changing levels of
glucose in the blood and secreted appropriate amounts of
insulin to ensure normal glucose metabolism.

Insulin, a hormone produced and secreted by specialized
pancreas cells called islets of Langerhans, converts sugars,
starches and other foods into the energy needed for everyday
life. These islets do not function properly in people with
insulin-dependent, or Type I, diabetes. These patients must
have injected insulin to stave off the long-term effects of
improper glucose metabolism, which includes blindness, kidney
disease, heart disease, nerve damage, limb loss and potentially

"After we confirmed that the baboon was indeed diabetic, we
surgically placed the encapsulated islets into the animal's
peritoneal cavity," said Dr. William Kendall Jr., senior
surgical resident at Duke who prepared the results of the
team's research for presentation Friday (June 15) at the
bi-annual scientific meeting of the International Pancreas and
Islet Transplant Association. The researchers also prepared a
poster session on the novel baboon model they created for this

"To date, the animal's blood sugar levels have remained in
the normal range, and it hasn't required any additional islet
cell therapy," Kendall said. "We are very encouraged by these

Five more baboons are in various stages of study at

According to Emmanuel Opara, associate research professor of
experimental surgery and cell biology at Duke University
Medical Center, who began and leads Duke's islet cell
transplant program, this approach promises a practically
unlimited supply of islet cells that could put an end to the
daily routine of multiple insulin injections for the more than
1 million Americans with Type I diabetes. Islet cell
transplantation could also help approximately one-quarter of
the 15 million Americans with Type II (adult onset) diabetes
who require daily insulin injections.

A majority of people with Type II diabetes are not
candidates for islet cell transplants, since the root of their
disorder is not improper production of insulin, but rather the
inability of receptors in the body to properly process

"We envision being able to place these islets within the
abdomen of humans using existing laparoscopic, or minimally
invasive, techniques," Opara said. "At this point we do not
know how often patients with diabetes would need this therapy,
but the baboon data to date are very encouraging. The first
baboon is still diabetes-free after only the initial

During the late 1990s, Opara's team developed the technique
to envelope the islets within an alginate sphere. After
isolating the insulin-producing islet cells from the rest of
the pig pancreas tissue, they are bathed in the alginate
solution and gently forced through a system that creates a
protective sphere around each islet.

"The spheres have surface pores that are large enough to
allow glucose to enter and insulin to exit, but are small
enough to keep immune system cells from entering the spheres
and attacking the islet cells," Opara said. "The spheres could
be placed anywhere in the body where they come into contact
with blood or other bodily fluids."

In the case of the first baboon, it required about 250,000
islets taken from about three pigs. While it is not yet known
how many pig pancreases would be needed to yield enough islets
for a human, there are more than 90 million pigs used for food
production each year in the United States, more than enough
needed to treat the number of Americans with diabetes, the
researchers said.

Once the baboon became diabetic, its fasting glucose levels
jumped from about 100 milligrams per deciliter of blood to
about 400 mg/dL. During the nine-month period following the
islet cell transplant, glucose levels averaged 115mg/dL. The
researchers did not detect any signs that the baboon's immune
system reacted to the pig islets.

The pancreas is a complex gland -- it not only regulates
blood glucose levels, but also secretes enzymes that are
crucial to digestion. This complexity has led to difficulties
in developing a reliable animal model to study ways to treat
the disease.

Some researchers have developed primate models of diabetes
where the entire pancreas is removed, and while that does
create the disease, it also causes significant digestive
problems for the animal. Still other researchers have employed
a chemical approach, using the compound streptozotocin, which
is known to destroy the islet cells. However, since it injected
systemically, streptozotocin causes complications to the
animal's liver and kidneys. It is also an unreliable approach
in baboons, if used alone.

The baboon model created by the Duke researchers is

"We took an approach that employed the best of both earlier
attempts, while avoiding the negative side effects of each,"
explained Kendall. "First, we removed about 90 percent of the
pancreas, which left enough of the gland to maintain normal
digestive functions. Then, we directly applied the
streptozotocin to the remaining 10 percent of the pancreas
during the operation – initially killing the majority of
remaining islets cells while minimizing the systemic effects.
We then administered additional small doses of streptozotocin
systemically, as needed, to destroy any residual cells."

The researchers monitored an important biochemical marker to
demonstrate that it was indeed the pig islets, and not some
possibly surviving baboon islets, that were responsible for
producing the insulin.

While in the pancreas, a precursor form of insulin
(proinsulin) is attached to a peptide known as C-peptide. When
this combined unit enters the bloodstream, it splits apart –
the insulin goes about its business of regulating glucose
levels, while the C-peptide travels through the liver to other
tissues where it may help with other physiological

"For instance, we know that C-peptide can protect the
cardiovascular system from being damaged by the diabetes,"
Opara said. "Patients with diabetes inject purified insulin,
not the complete proinsulin unit, and that is a reason why they
must watch the long-term complications of the disease. They do
not receive the C-peptide protection.

"In the baboon that received the islet cell transplant, we
detected normal levels of porcine C-peptide, which indicates
that porcine insulin was maintaining the proper glucose levels
in the animal," Opara said. "The transplanted baboon also had
much tighter blood glucose regulation than the control animal
that was being treated with insulin injections alone."

Other Duke members of Opara's team include Drs. Brad
Collins, Hasan Hobbs and Randy Bollinger. The islet cell
research is supported by the Duke Department of Surgery and
MicroIslet Inc., a San Diego-based firm that has licensed the
rights of this technology from Duke.

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