Researchers have long sought to understand why insulin-secreting beta cells in the pancreas often fail to proliferate in people who go on to develop type 2 diabetes. Studying both humans and mice, HMS scientists at Joslin Diabetes Center now have identified one key biological mechanism that can prevent successful cellular division. Their study was published April 4 in Cell Metabolism.
“Very often,” says Rohit Kulkarni, an HMS professor of medicine, a Joslin senior investigator, and senior author of the study, “many of the beta cells that begin the cell cycle don’t complete it because the regulatory signals aren’t appropriate. The cells instead choose to die.”
Kulkarni’s lab had previously analyzed beta cells that were modified to lack an insulin receptor and didn’t divide as easily as normal beta cells. They found that, compared with normal beta cells, these cells generated significantly smaller amounts of two proteins that partner to help separate the cell’s chromosomes before cell division.
In their latest research, the Joslin team explored the actions of the two proteins—centromere protein A (CENP-A) and polo-like kinase-1 (PLK1)—in mice and in cells from humans and mice.
They found that mice that lacked the CENP-A protein could not compensate for insulin resistance by making more insulin-secreting cells. They also found lower levels of CENP-A and PLK1 proteins in cells from human donors with diabetes compared to levels in cells from healthy donors.
To better understand how insulin signaling affects beta-cell growth, the scientists studied a pathway involving a protein that acts as a transcription factor to regulate genes by binding to their DNA regions. This protein helps drive cell proliferation and can promote the expression of CENP-A and PLK1.
“We found that insulin signaling can initiate the binding of this transcription factor with CENP-A and PLK1, in both mouse and human beta cells,” Kulkarni says. “This binding is lost in beta cells lacking the insulin receptor, and the loss of binding leads to cell death.”
This type of regulation, say the researchers, is specific to beta cells and not seen in other metabolic cell types such as liver and fat cells.
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