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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-G2-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.

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