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 and the University of Chicago 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 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 earlier studies from Kulkarni and colleagues that small chemical change to RNA, 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, genetically engineered mice and 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 co-corresponding author Dario F. De Jesus, PhD, now an Assistant Professor of Medicine at UChicago. “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.”
