Previous studies of beta cell proliferation generally have focused on mechanisms that kick off the cell cycle that leads to successful cell division. "Most adult mammalian beta cells are in a quiescent phase, and so if you want to push them into the cell cycle, you need to shake them out of their sleep," explains the senior author.

"However, very often many of the beta cells that begin the cell cycle don't complete it, because the regulatory signals aren't appropriate," senior author notes. "The cells choose to die because that's an easier route than completing the cell cycle."

Seeking to understand this failure to divide, the lab previously analyzed beta cells that were modified to lack an insulin receptor and didn't divide as easily as normal beta cells. Among their findings, the scientists saw that these cells generated significantly smaller amounts than normal beta cells of two proteins that partner to help separate the cell's chromosomes just before the cell divides.

In their latest research published in the journal Cell Metabolism, the team performed many experiments to explore the actions of these two proteins, called centromere protein A (CENP-A) and polo-like kinase-1 (PLK1), in mice and in cells from humans and mice.

Among their experiments, the researchers studied beta cell signaling in mice that were modified to lack expression of the proteins and experienced insulin resistance by being placed on a high-fat diet, or aging, or becoming pregnant. "We showed that mice that lacked the CENP-A protein could not compensate for insulin resistance by making more insulin-secreting cells," senior author says.

Additionally, the team examined human beta cells and found lower levels of CENP-A and PLK-1 proteins in cells from donors with diabetes compared to cells from healthy donors.

To better understand how insulin signaling affects beta-cell growth, the scientists next studied a pathway involving a protein called FOXM1. This protein acts as a "transcription factor" that regulates genes by binding to their DNA regions. FOXM1 helps to drive cell proliferation, and it can promote the expression of CENP-A and PLK-1.

"We found that insulin signaling can initiate the binding of this transcription factor with PLK-1 and CENP-A, in both mouse and human beta cells," senior author says. "This binding is lost in beta cells lacking the insulin receptor, and the loss of binding leads to cell death rather than division."

"We also discovered that this type of regulation is, interestingly, specific to beta cells, and not seen in other metabolic cell types such as liver and fat cells," senior author says.

Given this new insight into how beta cells divide or fail to divide, "our next step will be to begin to ask whether we can target FOXM1 or other proteins in the pathway to enable a better progression through the cell cycle and to generate more beta cells," senior author says.

http://www.joslin.org/news/research-finds-key-barrier-to-proliferation-of-beta-cells.html

http://www.cell.com/cell-metabolism/fulltext/S1550-4131(17)30094-3