Joslin Scientists Find a Potential Pathway for Replenishing Insulin-Producing Cells
Study Reveals How Pancreatic Cells Preserve Their Identity
BOSTON — Diabetes is characterized by the loss or dysfunction of insulin-producing pancreatic beta cells, and finding a way to replenish or restore those cells has long been one of the holy grails of diabetes research. New research from investigators at Joslin Diabetes Center identifies a molecular mechanism that plays a key role in helping pancreatic cells maintain their identities while revealing a potential path toward generating new insulin-producing beta cells from neighboring alpha cells.
"The potential to transform pancreatic α-cell into insulin-producing β-cells offers a promising strategy for addressing as β-cell deficient diabetes and other metabolic disorders,” said corresponding author Rohit N. Kulkarni, MD, PhD, a senior investigator at Joslin and a professor of medicine at Harvard Medical School.
Published in Nature Metabolism, the study builds on prior work by Kulkarni and colleagues suggesting that a small chemical change to RNA, resulting in a mark called m6A, helps insulin-producing beta cells maintain their normal function and identity. In the new study, the researchers turned their attention to beta-cells' neighbors, called alpha cells. Alpha cells produce the hormone glucagon, which — in contrast to insulin — raises blood sugar levels. Long viewed primarily as beta cells' counterparts, alpha cells have attracted growing interest because they appear capable of changing identity, raising the possibility that they could someday serve as a source of new insulin-producing cells.
Conducting experiments in cultured cells and genetically engineered mice and then performing analyses of human pancreatic datasets, the researchers identified a key regulator of alpha-cell identity, called METTL14. When the team disrupted the protein in experimental models, alpha cells began losing the molecular features that distinguish them as alpha cells and acquired characteristics of insulin-producing beta cells. Consistent with those changes, mice lacking METTL14 specifically in alpha cells exhibited impaired glucagon responses and elevated insulin levels.
“What surprised us most was that changing these small chemical marks on RNA changed the basic program that tells an alpha cell what kind of cell it is,” said lead author and co-corresponding author Dario F. De Jesus, PhD, currently an assistant professor of medicine at the University of Chicago. “This gives us a new way to think about how pancreatic cells maintain their identity over time and what happens when that stability is disrupted.”
Together, the findings suggest that METTL14 is part of the molecular machinery that helps pancreatic cells maintain their identities. The work also provides new evidence that alpha cells may be capable of transitioning toward a beta-cell-like state under certain conditions.
"Our study revealed a delicate molecular balance, one that not only stabilizes alpha-cell identity but also potentially permits its plasticity under specific conditions,” Kulkarni said.
The findings add to growing evidence that pancreatic endocrine cells may be more flexible than once believed. Understanding the mechanisms that govern those cell-state changes could eventually contribute to regenerative approaches for diabetes.
The authors note that the work was conducted in experimental models and does not represent a therapeutic intervention. However, they conclude that understanding and potentially harnessing alpha-cell's ability to change identity may offer new avenues for restoring insulin-producing cells in the future.
Co-authors included Natalie K. Brown, Garrett Fogarty, Jiang Hu, Joan Sabadell-Basallote, Sevim Kahraman and Ling Xiao of Joslin Diabetes Center.
This research was supported by the National Institutes of Health, including grants R01 DK067536, UC4 DK116278, RC2 DK139552 and R00 DK135927. Kulkarni also acknowledges support from the Diabetes Research and Wellness Foundation Endowed Chair.
Dr. Kulkarni serves on scientific advisory boards for Novo Nordisk, Biomea and REDD Therapeutics. Kahraman is an employee of Boehringer Ingelheim Pharmaceuticals, Inc.
About Joslin Diabetes Center
Joslin Diabetes Center is world-renowned for its deep expertise in diabetes treatment and research. Part of Beth Israel Lahey Health, Joslin is dedicated to finding a cure for diabetes and ensuring that people with diabetes live long, healthy lives. We develop and disseminate innovative patient therapies and scientific discoveries throughout the world. Joslin is affiliated with Harvard Medical School and one of only 18 NIH-designated Diabetes Research Centers in the United States.
