May 13, 2002 STANFORD, Calif. - Researchers at Stanford University Medical Center have created fruit flies with a condition that mimics human diabetes. Although it's a big evolutionary leap from flies to humans, the researchers say their tiny diabetic "patients" will help scientists understand how insulin-releasing cells develop - a first step toward replacing cells lost in human diabetes.
"The idea is that the more you know about normal development the better chance you have to make stem cells develop into insulin-producing cells," said Eric Rulifson, PhD, a postdoctoral fellow in developmental biology and lead author of a paper due out in the May 10 issue of Science.
Insulin's normal role in the body is to help muscle, liver and fat cells take up sugar from the blood and use it for energy. In Type I diabetes (also known as juvenile diabetes), the immune system destroys pancreatic cells that produce insulin. Without insulin, sugar accumulates in the blood, damaging the eyes, kidneys, blood vessels and nerves, and preventing the body from converting sugar to energy. People with Type I diabetes must inject insulin in order to survive.
One potential cure involves using stem cells to generate replacements for the lost insulin-producing cells. The problem is coaxing those stem cells to develop into pancreatic cells rather than some unrelated cell type. To entice those cells down the correct developmental pathway, researchers need to know how the cells normally develop.
This is where the fruit fly excels, said Roel Nusse, PhD, professor of developmental biology and co-author on the paper. Although flies are less complicated than humans, they retain the same basic biological process and are much easier to study. "There are many examples of functions that are conserved between flies and humans," said Nusse, who is also an investigator at the Howard Hughes Medical Institute.
As an example, Nusse points out that one branch of the immune system is nearly identical in flies and humans, including the genes and molecular defenses used by the two systems. Because of this similarity, researchers have been able to learn more about the human immune system by studying flies.
Rulifson said the same could be true for insulin-producing cells. "If the fly cells are using the same molecules and genes as humans, then there's a good chance that much of the pathway of development is conserved," he said.
To make the diabetic flies, Rulifson first identified a group of cells in the brain that produce insulin. He then specifically destroyed only those insulin-producing cells in the fly larvae. These larvae were significantly smaller than their normal counterparts and took longer to develop into full-fledged flies. What's more, the fly larvae that lacked insulin had high blood-sugar levels, comparable to human diabetes.
When Rulifson looked at where the insulin-producing cells were located in the fly brain, he found that they sent projections to the heart, where the nerves released insulin into the larvae's circulatory system. This is similar to how the pancreatic cells release insulin into the human bloodstream.
The nerves also sent projections to a group of cells that release a protein similar to human glucagon. This substance has the opposite effect of insulin - causing cells to release stored sugar into the blood when blood-sugar levels are low. Together, the two opposing hormones keep human blood-sugar levels steady, and may do the same in flies.
Rulifson called these similarities between fly and human hormonal systems "the tip of the iceberg." He said there is enough similarity to suspect his diabetic flies will be good models for the human disease. "This fly model could help us understand the origin of insulin-producing cells in people," he said.
Rulifson is supported as an advanced postdoctoral fellow by the Juvenile Diabetes Research Foundation.
Stanford University Medical Center integrates research, medical education and patient care at its three institutions - Stanford University School of Medicine, Stanford Hospital & Clinics and Lucile Packard Children's Hospital at Stanford. For more information, please visit the Web site of the medical center's Office of Communication & Public Affairs at http://mednews.stanford.edu.
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