Diabetes is characterized by persistent high blood sugar levels that occur when certain cells in the pancreas—the insulin-producing β cells—can no longer secrete insulin. New research, published yesterday in Nature Cell Biology, shows how some pancreatic α and δ cells can take over insulin production for the damaged β cells.
"What we are showing here is that the state of differentiation of a given cell is not carved in stone,” says senior author Pedro Herrera of the University of Geneva. “Cell identity, at all stages of life, is modulated by the immediate cellular environment, particularly by inhibitory signals. Cell identity maintenance is therefore an active process of inhibition throughout the life of the cell, and not an intrinsic or passive state of differentiation. This ability of specialized cells to change their function could prove crucial for treating other pathologies that are due to massive or inappropriate cell death, such as Alzheimer's disease or myocardial infarction.”
The pancreas contains several cell types that produce different hormones that regulate blood sugar levels. Among these are the α cells, which produce glucagon, the β cells, which produce insulin, and the δ cells, which produce somatostatin. In the absence of functional β cells, blood sugar levels are persistently high.
The team conducted gene expression analyses before and after the disappearance of β cells. In α cells, the disappearance of β cells caused opposing modifications: the overexpression of genes typical of insulin-producing β cells, and also the overexpression of genes typical of glucagon-producing α cells. But what signal induces cell conversion? After exploring different possibilities, the researchers determined that the only explanation is that the reprogramming capacity is intrinsic to the very pancreatic islet where these cells are located.
"In the same graft, only islets without β cells displayed reprogramming,” Herrera notes. “No cell conversion occurred in neighboring islets containing all their β cells.”
The researchers then blocked the insulin receptors located on α cell surfaces in non-diabetic mice. Some of these α cells then began to produce insulin, indicating that insulin prevents the reprogramming of α cells. “These cells became hybrids,” Herrera says. “They partially, but not fully, changed their identity, and the phenomenon was reversible depending on the circumstances influencing the cells.”
Image: Mouse pancreatic islet in which the glucagon (purple)-producing alpha-cells have been labeled with a fluorescent tag (green). Some of them have started to produce insulin (red), and they appear as yellow (green-and-red merge). Image courtesy of UNIGE.