Bringing scientists a step closer to new treatments for diabetes, researchers at the University of Pittsburgh School of Medicine and The Mount Sinai Medical Center have discovered a novel mechanism that regulates the replication of insulin-producing beta cells in the pancreas. The findings were recently published online ahead of print in Diabetes, a journal of the American Diabetes Association.
Regenerating beta cells to restore insulin production has moved to center stage in the quest for therapies for both Type 1 and 2 diabetes, said lead author Nathalie Fiaschi-Taesch, Ph.D., assistant professor, Division of Endocrinology and Metabolism, Pitt School of Medicine.
"Ideally, we would be able to do this by collecting cells from donor pancreatic tissue and growing them in the lab or better yet, giving a patient a pill to stimulate their own beta cells to replicate," she said. "In the past, this has proven to be very challenging. Our findings provide new insights into how one may be able to do this. "
After a 2009 paper in which a team led by Dr. Fiaschi-Taesch and Andrew F. Stewart, M.D., formerly of Pitt and now Irene and Dr. Arthur M. Fishberg Professor of Medicine and director of the Diabetes, Obesity and Metabolism Institute at The Mount Sinai Medical Center in New York, successfully induced human beta cells to replicate in the lab by elevating the level of a protein called cdk-6. In two current reports in Diabetes, they continued to examine the workings of the cell cycle proteins involved in the replication machinery.
What they found surprised them. Scientists had assumed the proteins resided in the cell's nucleus, where they could act upon genes and molecules to stimulate – or in the case of beta cells, prevent – cell replication. Their experiments showed that the cell cycle proteins were actually in the cell's cytoplasm, the fluid around the nucleus and contained within the cell membrane.
"It's like looking under the hood of a car for the engine and instead finding all the parts scattered around the back seat: it's no wonder the car won't go," Dr. Stewart explained. "Now we have to find ways to get those parts hooked up and back under the hood so that they can once again function as the engine that drives beta cell replication."
Increasing levels of cdk-6 led that molecule and other key (or critical) cell cycle proteins to move into the nucleus to foster replication, but in the quiescent or non-replicating cell, the only ones that remained in the nucleus were inhibitors of replication. Understanding how and why those inhibiting proteins block replication could in turn lead to ways to block their activity, providing a novel approach for reviving beta cell regeneration, Dr. Fiaschi-Taesch said.
Dr. Stewart noted that the relocation of cell cycle proteins outside the nucleus in the beta cell might hold true for other kinds of cells.
"It makes me curious about whether we can turn replication back on in other cells that aren't known to regenerate, such as neurons," he said. "I'd also like to know why these proteins continue to be produced by the quiescent cell if they aren't playing a role in cell replication."
In the second Diabetes paper, the team described the intracellular localization of all the cell cycle proteins in the beta cell, a biochemical atlas that could guide other researchers.
Co-authors include Jeffrey W. Kleinberger, B.S., Fatimah Salim, B.S., Ronnie Troxell, B.S., Rachel Wills, B.S., Mansoor Tanwir, M.D., Gabriella Casinelli, B.S., Amy E. Cox, M.D., and Karen K. Takane, Ph.D., Harish Srinivas, Ph.D., all of the Division of Endocrinology and Metabolism, Pitt School of Medicine; and Donald K. Scott, Ph.D., of Mount Sinai Medical Center.
The project was funded by the National Institute of Diabetes and Digestive and Kidney Diseases, part of the National Institutes of Health, though grants U-01 DK 089538, R-01 DK55023, R56 DK065149 and T32-07052; the Juvenile Diabetes Research Foundation; the American Diabetes Association, and the University of Pittsburgh.
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 1998. In rankings recently released by the National Science Foundation, Pitt ranked fifth among all American universities in total federal science and engineering research and development support. 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 http://www.medschool.pitt.edu.
About Mount Sinai
The Mount Sinai Medical Center encompasses both The Mount Sinai Hospital and the Icahn School of Medicine at Mount Sinai. Established in 1968, the Icahn School of Medicine is one of the leading medical schools in the United States, and is noted for innovation in education, biomedical research, clinical care delivery, and local and global community service. It has more than 3,400 faculty in 32 departments and 14 research institutes, and ranks among the top 20 medical schools both in National Institutes of Health (NIH) funding and by U.S. News & World Report.
The Mount Sinai Hospital, founded in 1852, is a 1,171-bed tertiary- and quaternary-care teaching facility and one of the nation's oldest, largest and most-respected voluntary hospitals. In 2012, U.S. News & World Report ranked The Mount Sinai Hospital 14th on its elite Honor Roll of the nation's top hospitals based on reputation, safety, and other patient-care factors. Mount Sinai is one of 12 integrated academic medical centers whose medical school ranks among the top 20 in NIH funding and by U.S. News & World Report and whose hospital is on the U.S. News & World Report Honor Roll. Nearly 60,000 people were treated at Mount Sinai as inpatients last year, and approximately 560,000 outpatient visits took place.
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Journal
Diabetes