Bigger betas are better – Protein found to provide pancreatic cells with protection against diabetes
(Philadelphia, PA) –While studying the proteins in pancreatic beta (β) cells – the cells that produce insulin – researchers at the University of Pennsylvania Medical Center discovered how the protein enzyme Akt1 can cause mice β cells to grow larger and produce more insulin. Their findings, published in this month’s Nature Medicine, have direct implications for the current need to increase the number of human pancreatic cells available for transplant to diabetic patients.
"The mice bred to produce excess Akt1 protein were more tolerant of glucose and more resistant to diabetes – in fact, we simply could not give them diabetes when we tried," said Morris J. Birnbaum, MD, PhD, associate director of the Penn Diabetes Center in the Penn Departments of Medicine & Cell and Molecular Biology and an investigator in the Howard Hughes Medical Institute. "The increase in Akt1 directly leads to an increase in the size, amount, and total production of insulin by β cells."
In the United States, diabetes is the seventh leading cause of death and currently effects over 15 million people. Medical science recognizes two forms of diabetes. Type 1 diabetes results from the immune system’s destruction of pancreatic β cells. Type 2 diabetes results when the body cannot either produce enough insulin or properly use the insulin it does produce. Without insulin, the body cannot utilize glucose – blood sugar – which can lead to a variety of debilitating illnesses, including heart disease, blindness, and kidney failure.
Recently, surgeons have met with success in treating the disorder by transplanting clusters of pancreatic cells, called islets, into diabetic patients. Transplanted islets, which include β cells, have been shown to reestablish the production of insulin in the pancreas. Unfortunately, the demand for islets far outweighs the supply.
"What makes our findings so interesting, clinically, is the potential to enlarge our pool of β cells for transplant," said Birnbaum. "We see that Akt1 causes more plentiful, and bigger, β cells – they are plump, well fed cells." The Penn research team, spearheaded by graduate student Robyn Tuttle, began this study to look specifically at the role of Akt1 in living organisms in order to evaluate the protein’s possible role in the β cell loss that causes diabetes. Previously, studies of Akt1 in cell cultures determined that the protein had an important role in assisting the function of insulin and helping cells convert glucose into energy. After failing to induce diabetes in their experimental mice by killing β cells, Birnbaum and his colleagues found that there was a significant increase in both β cell size and the total mass of the islets.
According to Birnbaum, Akt1 is a potent factor in deciding the size of cells in mammals. One view is that insulin signaling through Akt1 leads to a coordinated increase in cellular metabolism, which results in bigger cells and an increase in the amount of proteins the cells make. The interplay between insulin and glucose is, in essence, the story of how our bodies derive energy from the food we eat. The Akt1 protein has an important, behind-the-scenes, role in putting that story in motion and coordinating the events.
Perhaps what has surprised the researchers most is how they also see evidence that Akt1 promotes the creation of entirely new β cells.
"The number of β cells that you will have at any given time are determined by three things: how fast they divide, how fast they die, and how fast your body can generate completely new ones," said Birnbaum. "Since the death rate and the division rate did not change in our mice, it is possible that Akt1 also promotes the growth of new β cells."
Funding for this research was provided by the National Institutes of Health.
The University of Pennsylvania Health System is distinguished not only by its historical significance – first hospital (1751), first medical school (1765), first university teaching hospital (1874), first fully integrated academic health system (1993) – but by its position as a major player on the world stage of medicine in the 21st century. Committed to a three-part mission of education, research, and clinical excellence, UPHS has excelled in all three areas. Penn ranked second among all American medical schools that received funds from the National Institutes of Health, perhaps the single most important barometer of research strength.