BOSTON, Mass. – In people who put on a lot of weight, or whose bodies start developing the inability to use insulin effectively that leads toward type 2 diabetes, the pancreas typically ramps up its supply of insulin-generating “beta” cells—at least in part by replication of existing beta cells. Researchers at Joslin Diabetes Center and their colleagues now have identified a cell-cycle protein that is essential for beta-cell replication to respond successfully to insulin resistance. The finding may point toward eventual therapies for preventing or treating type 2 diabetes.
In a paper published online in Diabetes on January 26, biologists in the labs of Joslin Principal Investigator Rohit N. Kulkarni, M.D., Ph.D., and Anil Bhushan, Ph.D., at the University of California at Los Angeles used a genetic approach to show that a protein called cyclin D2 is needed for this beta-cell response in mice.
Cyclin D2 is a member of a small family of proteins that aid in the cell cycle, by which cells divide into two. Earlier studies had demonstrated that cyclin D2 is particularly important to the replication of beta cells but had not directly addressed its role in insulin resistance.
The researchers began with two existing mouse models that develop insulin resistance—one mild case and one more severe case, reflecting the spectrum observed in humans with type 2 diabetes. Each of the models ends up generating many more beta cells. When these mice were crossed with mice lacking cyclin D2, all their progeny developed diabetes because they produced dramatically fewer beta cells.
This work provides direct evidence in mice that cyclin D2 is needed for a successful response to a broad spectrum of insulin resistance, and points toward potential therapies that can be harnessed for preventing and curing type 2 diabetes.
“Beta-cell replication occurs naturally in diet-induced obesity and in pregnancy, so this process gives us a target for therapy,” Dr. Kulkarni notes.
It is still unclear whether cyclin D2 is expressed in human beta cells, so the researchers next will look for its analog in humans. “Our challenges are first, to figure if there’s a similar protein in humans that is exclusive to the beta cells, and second, to find an injectable therapy that can home in on the beta cells,” he says.
Dr. Kulkarni adds that the research also holds implications for work in his own lab and many other labs that seek to create beta cells from induced pluripotent stem (IPS) cells, adult cells transformed to a state like that of embryonic stem cells. “One could envision expanding beta cells created from IPS cells in vitro and then transplanting them,” he says. “In that case, it will be extremely useful to identify proteins like cyclin D2 that are helpful for replication.”
Senta Georgia, Ph.D. of UCLA and Charlotte Hinault, Ph.D. of Joslin are co-lead authors on the paper. Drs. Kulkarni and Bhusan are co-corresponding authors. Dan Kawamori, M.D., Ph.D., Jiang Hu, M.D., and John Meyer of Joslin, and Murtaza Kanji of UCLA, also contributed. Funding was provided by the National Institutes of Health and the Juvenile Diabetes Research Foundation.