They also found several cocktails of molecules that drive human beta cells to replicate, as well as important differences between mouse and human beta cells that could influence how these approaches are best used to treat diabetes, which is caused by insufficient insulin production leading to abnormal blood sugar levels.
"Our team was the first to show that adult human beta cells can be induced to proliferate or grow at substantial rates, which no one thought possible before," said senior author Andrew F. Stewart, M.D., professor of medicine and chief of the Division of Endocrinology and Metabolism, Pitt School of Medicine. "Now our effort has been to unravel these regulatory pathways to find the most effective strategy that will allow us to treat – and perhaps cure – diabetes by making new insulin-producing cells."
In a series of experiments, lead author Nathalie M. Fiaschi-Taesch, Ph.D., assistant professor of endocrinology, and the team discovered that combining elevated amounts of the regulatory molecules cdk4 or cdk6 with a variety of D-cyclin proteins, particularly cyclin D3, stimulates human beta cell replication in test tubes.
"We didn't expect cyclin D3 to ramp up beta cell replication so strongly when it was used with either cdk4 or cdk6," Dr. Fiaschi-Taesch said. "There was no known role for cyclin D3 in human beta cell physiology."
Cyclin D2 is present in and essential for rodent beta cell replication and function, but the team showed that molecule is barely detectable in human cells, and beta cell replication could be sustained for at least four weeks in a model in which mice were transplanted with human beta cells engineered to overproduce cdk6. Blood sugar normalized in the diabetic mice transplanted with surprisingly small numbers of human beta cells, indicating that the cells functioned properly to produce needed insulin.
Mice don't appear to make cdk6 naturally, but they do have cdk4 and cyclins D1 and D2, so standard rodent studies of beta replication might have led scientists to pursue the wrong molecules in their quest to stimulate human beta cell replication, Dr. Stewart noted.
He and his colleagues continue to explore many other regulatory proteins that could play a role in encouraging or thwarting beta cell replication.
Other authors of the paper include Fatimah Salim, Jeffrey Kleinberger, Ronnie Troxell, Karen Selk, Edward Cherok, Karen K. Takane, Ph.D., and Donald K. Scott, Ph.D., all of the Division of Endocrinology and Metabolism, Department of Medicine, Pitt School of Medicine; and Irene Cozar-Castellano, Ph.D., Unidad de Investigacion, Hospital Universitario Puerta del Mar, Cadiz, Spain.
The research was funded by grants from the National Institute of Diabetes and Digestive and Kidney Diseases, the Juvenile Diabetes Research Foundation, the Spanish Ministry of Science and Innovation, and the Pam and Scott Kroh and the Don and Arleen Wagner family foundations.
About the University of Pittsburgh School of Medicine
As one of the nation's leading academic centers for biomedical research, the University of Pittsburgh School of Medicine integrates advanced technology with basic science across a broad range of disciplines in a continuous quest to harness the power of new knowledge and improve the human condition. Driven mainly by the School of Medicine and its affiliates, Pitt has ranked among the top 10 recipients of funding from the National Institutes of Health since 1997 and now ranks fifth in the nation, according to preliminary data for fiscal year 2008. Likewise, the School of Medicine is equally committed to advancing the quality and strength of its medical and graduate education programs, for which it is recognized as an innovative leader, and to training highly skilled, compassionate clinicians and creative scientists well-equipped to engage in world-class research. The School of Medicine is the academic partner of UPMC, which has collaborated with the University to raise the standard of medical excellence in Pittsburgh and to position health care as a driving force behind the region's economy. For more information about the School of Medicine, see www.medschool.pitt.edu.
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