Successful test with diabetic baboon

DUKE UNIVERSITY Medical Centre researchers have reported 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 soon.

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 death.

"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 senior surgical resident at Duke who presented the results at the bi-annual scientific meeting of the International Pancreas and Islet Transplant Association at Innsbruck, Austria . The researchers also prepared a poster session on the novel baboon model they created for this study.

"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 results." Five more baboons are in various stages of study at Duke.

According to Emmanuel Opara, associate research professor of experimental surgery and cell biology at Duke University Medical Centre, 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 insulin.

"We envision being able to place these islets within the abdomen of humans using existing laparoscopic, or minimally invasive, techniques," Opara said. During the late 1990's, 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. It is not yet known how many pig pancreases would be needed to yield enough islets for a human.

Once the baboon became diabetic, its fasting glucose levels jumped from about 100 milligrams per decaliter 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.

The baboon model created by the Duke researchers is unique. - "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 activities.

"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.

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