Mar. 1, 2000 GAINESVILLE, Fla.---University of Florida researchers have reversed diabetes in mice with a simple injection of cells that soon produce enough insulin to regulate blood sugar effectively, they reported today (3/1) in the journal Nature Medicine.
To do so, they harvested pancreatic cells in their earliest stages of development from the mice themselves, then nurtured them in the laboratory until they evolved into small, insulin-secreting organs known as islets of Langerhans.
Researchers collected the cells into a syringe and injected them just beneath the surface of the animals' skin. Within a few days they began to function like an endocrine pancreas - the pancreas' islets of Langerhans, said UF immunologist Ammon B. Peck.
"This is very exciting, because the cells can be placed very simply into an individual in an area with no need for a complicated surgical procedure," he said.
People with diabetes lose their ability to regulate how the body uses and stores sugar and other nutrients for energy when their immune system launches a self-directed attack, destroying the insulin-producing cells in the pancreas. Researchers were encouraged to find that no such assault occurred on the implanted cells -- known as stem cells -- during the study period, which lasted more than three months.
The findings open up the possibility of someday permanently reversing insulin-dependent diabetes for the more than 750,000 Americans who battle the disease. Many suffer major side effects, including damage to blood vessels, which can lead to heart disease, stroke, blindness, kidney failure and poor circulation to the lower limbs.
"This indicates there is some mechanism, something about growing them from stem cells in culture, that tricks the autoimmune response, at least for some time," Peck said.
Stem cells have the ability to evolve into an array of cell types as they mature. After they were placed in the mice, the cells secreted insulin and thrived as new blood vessels grew toward them. Within a week to 10 days, all the mice were able to regulate levels of sugar, or glucose, in the bloodstream for the time of the study.
"If you eat a candy bar it raises the amount of glucose in the blood," explained Peck, a professor of pathology, immunology and laboratory medicine at UF's College of Medicine. "The islets respond rapidly to that because they sense how much sugar is in the blood and produce insulin, and insulin allows for proper utilization of glucose for energy by other cells in the body."
The ability to control the growth and development of pancreatic stem cells potentially provides an unlimited resource for insulin-producing cells for people with diabetes, the authors wrote in the journal. Peck's co-authors included UF pediatric endocrinologist Dr. Desmond A. Schatz. The study was supported by the National Institutes of Health; Vijayakumar Rimiya, of Ixion Biotechnology Inc. at UF's Progress Park in Alachua, Fla.; and Karl Arfors, of Q-Med, Scandinavia, in San Diego.
The method is comparable to techniques used to derive cells for skin grafts or for bone marrow transplantation, said Peck, although there is a key difference: The pancreatic stem cells grow into a complete organ and become fully functional in culture, prior to placing them back into the body.
"Our first observation was the fact that one can take a single stem cell and induce it to grow and differentiate into a full-functioning organ, containing all the differentiated, end-stage cells found in the exocrine pancreas," he said. "The only situations we have up to now that would be comparable have been studies of stem cells that give rise to skin grafts and stem cells that give rise to blood cells. But even in both those situations they're really not the same. For example, bone marrow stem cells cannot evolve into all end-stage cells until after they are implanted into the body."
Earlier UF research laid the groundwork for the latest findings. Those studies, conducted in the early 1990s, showed that laboratory-grown pancreatic tissue could reverse diabetes in mice if transplanted into the kidney, creating a pseudo-pancreas. In contrast, the new approach is only minimally invasive because the cells are placed just under the skin, Peck said.
"Obviously there are still a number of hurdles we have to overcome and a lot of theoretical questions we have to have answers to before we would begin implanting the cells in humans," Peck said. He added that scientists are duplicating the study in the laboratory using human cells, and hope to begin implantation in primates soon, which would pave the way for eventual human trials. Islet stem cells currently are obtained from human organ donors.
"We know adults, even those with diabetes who have lost their insulin-secreting beta cells, maintain stem cells in the pancreas," he said. "We know the stem cells are there; the question is, can we get them out and grow them up for an individual patient? Transplantation raises several concerns, including immune rejection of the graft and finding a site suitable to accommodate adequate numbers of implanted islets. It's clear that a small injection of cells into the arm or leg would suffice."
The availability of pancreatic transplants and islet stem cells has been limited by current human organ donation rates, said Dr. Camillo Ricordi, scientific director and chief academic officer at the Diabetes Research Institute at the University of Miami School of Medicine.
"Now that we have established proof of principle that human insulin-producing cells can be used to treat patients with diabetes, there comes a critical need to develop alternative sources of insulin-producing tissues," said Ricordi, a professor of surgery and medicine. "If in fact we transplanted, based on human organ donation rates, it would be feasible to treat only a very small fraction of patients with diabetes. This study is an exciting first step toward the development of new sources of insulin-producing cells that could eventually be used in the clinical setting."
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