September 15, 2004

New Fruitfly Model of Diabetes Has Future Implications for Pancreatic Islet Cell Transplantation

(Philadelphia, PA) - A newly completed picture of how fruitflies control their blood sugar will inform researchers and clinicians about the basics of metabolism and how it relates to disease. Eric Rulifson, PhD, Assistant Professor of Cell and Developmental Biology at the University of Pennsylvania School of Medicine, and his colleague Seung Kim, PhD, from Stanford University, discovered an interconnected network of cells that tell the fly to take up or release sugar, as needed.

Two years ago Rulifson and Kim showed that a group of cells in the brain of the fly make insulin, which parallels the role of beta cells in humans. Now, in the September 16 issue of Nature, the researchers describe cells that produce a glucagon-like hormone, which are akin to alpha cells in mammals. These two cell types within the pancreatic islets are the main cellular sensors of blood-sugar levels. Together the fly’s insulin- and glucagon-producing cells could be seen to represent a primitive pancreatic islet.

After eating food, insulin notifies muscles, fat cells, and the liver to take up excess sugar in the blood and store it as glycogen. Conversely, when the sugar level in blood dips between snacks, glucagon notifies the muscles and liver to break down stored energy like glycogen and fat to release as glucose. However, when this finely tuned system goes wrong, all-too-familiar diseases arise: diabetes when there is too much sugar; hypoglycemia when there is too little.

Because of the unexpected similarities between the insect and human pancreas, Rulifson explains that now the fly can serve as a simple model of how sugar is regulated at a very basic level. “At this point investigators would like to understand how this ancient mechanism for cells that sense the nutrient and energy status of an animal can adjust an animal’s growth and metabolic state,” he says. “Now we have a model for that.”

Coaxing stem cells to become pancreatic islet cells for transplantation is potentially a permanent treatment for diabetes. As a developmental biologist, Rulifson is now concentrating on how the primitive pancreatic cells in the fly develop within an embryo. He and colleagues are sorting out the intricacies of what genes program the ultimate development of these mature cells from their progenitor cells. A better understanding of this process will help guide screening the human genome for genes that have a similar function in how alpha and beta cells develop.

“This will be useful information for researchers trying to program undifferentiated embryonic stem cells from other tissues to grow islet cells for cell-replacement therapies,” explains Rulifson. “We’re trying to identify a molecular roadmap for a normally developing beta cell, which might guide a stem cell to acquire the fate for making insulin. We hope that this Drosophila model will bring useful insights to the table.”

This research was funded by the Juvenile Diabetes Research Foundation, the Pew Charitable Trusts, and the Verto Institute.

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