A widely held assumption that the lack of insulin production characteristic of type 2 diabetes (T2D) is caused by the mass death of β cells in the pancreas may not need rethinking, researchers claim. Studies in mouse models of the disease led by scientists at Columbia University have found that in T2D the islet β cells aren’t necessarily dying off in large numbers, but are in fact reverting to a more progenitor-like state, and could potentially be prompted to redifferentiate back into active insulin-producing cells.
The team’s findings were made through an analysis of the role in T2D of Fox01, a transcription factor that integrates signals regulating β cell mass and stress response. Their studies in mice showed that during times of nutritional balance and when the body isn’t subjected to other forms of metabolic stress, Fox01 in β cells localized in the cytoplasm. However, as a result of nutritional or metabolic stresses such as hyperglycemia, pregnancy, or aging, Fox01 relocated to the nucleus and eventually disappeared. This loss of Fox01 was accompanied by an up to 30% loss in β cell mass and 50% increase in α cell mass, resulting in fasting hyperglycemia, decreased fed insulin levels and pancreatic insulin content, and increased fed glucagon levels and pancreatic glucagon levels.
Importantly, mice engineered to lack Fox01 specifically in their β cells also developed hyperglycemia and demonstrated reduced β cell mass as a result of physiological stress such as pregnancy or aging. However, the most surprising finding emerging from cell lineage tracing experiments was that this observed loss in β cell mass wasn’t due to large-scale death of β cells, but rather their dedifferentiation into progenitor-like cells that expressed neurogenin3, Oct4, Nanog, and L-Myc. A subset of these Fox01 deficient β cells also developed into α cells, resulting in overproduction of glucagon and hyperglucagonemia.
Critically, the same set of events coinciding with loss of Fox01 was also identified in a number of other mouse models of T2D, indicating that it may be a key process in development of the disease, report Domenico Accili and colleagues. In essence, the team write in their published paper in Cell, “FoxO1 is required to maintain β cell identity and prevent β cell conversion into non-β pancreatic endocrine cells in response to chronic pathophysiologic stress.”
The findings thus brings into question one of the current therapeutic approaches to treating the disease, which is essentially to force the remaining β cells to work harder and churn out more insulin. “Its like flogging a dying horse,” Dr. Accili notes. “You can push β cells only so far.” Instead, the researchers suggest, it may be possible to identify ways of prompting the dedifferentiated β cells to redifferentiate back into functional insulin-producing cells. “What that agent could be, we don’t know; but we have some inkling from our work that certain signaling pathways, such as the wnt or notch pathways, could be targeted for this purpose,” Dr. Accili adds. And the fact that a subset of dedifferentiated β cells generate α cells and produce glucagon indicates that they also retain the potential to be redifferentiated back into β cells.
“Our findings indicate that there is an ample time window between functional depletion of insulin in β cells and their demise,” the researchers write. “These observations offer a glimmer of hope that salvaging dedifferentiated β cells might provide an approach to treating β cell dysfunction in diabetes...We propose that dedifferentiation trumps endocrine cell death in the natural history of β cell failure and suggest that treatment of β cell dysfunction should restore differentiation, rather than promoting β cell replication."