Glucose Regulates Cyclin D2 Expression in Quiescent and Replicating Pancreatic β-Cells Through Glycolysis and Calcium Channels

Understanding the molecular triggers of pancreatic beta-cell proliferation may facilitate the development of regenerative therapies for diabetes. Genetic studies have demonstrated an important role for cyclin D2 in beta-cell proliferation and mass homeostasis, but its specific function in beta-cell division and mechanism of regulation remain unclear. Here, we report that cyclin D2 is present at high levels in the nucleus of quiescent beta-cells in vivo. The major regulator of cyclin D2 expression is glucose, acting via glycolysis and calcium channels in the beta-cell to control cyclin D2 mRNA levels. Furthermore, cyclin D2 mRNA is down-regulated during S-G(2)-M phases of each beta-cell division, via a mechanism that is also affected by glucose metabolism. Thus, glucose metabolism maintains high levels of nuclear cyclin D2 in quiescent beta-cells and modulates the down-regulation of cyclin D2 in replicating beta-cells. These data challenge the standard model for regulation of cyclin D2 during the cell division cycle and suggest cyclin D2 as a molecular link between glucose levels and beta-cell replication. (Endocrinology 152: 2589-2598, 2011)