title: Glucose regulates cyclin D2 expression in quiescent and replicating pancreatic β-cells through glycolysis and calcium channels.
abstract: Understanding the molecular triggers of pancreatic β-cell proliferation may facilitate the development of regenerative therapies for diabetes. Genetic studies have demonstrated an important role for cyclin D2 in β-cell proliferation and mass homeostasis, but its specific function in β-cell division and mechanism of regulation remain unclear. Here, we report that cyclin D2 is present at high levels in the nucleus of quiescent β-cells in vivo. The major regulator of cyclin D2 expression is glucose, acting via glycolysis and calcium channels in the β-cell to control cyclin D2 mRNA levels. Furthermore, cyclin D2 mRNA is down-regulated during S-G(2)-M phases of each β-cell division, via a mechanism that is also affected by glucose metabolism. Thus, glucose metabolism maintains high levels of nuclear cyclin D2 in quiescent β-cells and modulates the down-regulation of cyclin D2 in replicating β-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 β-cell replication.
authors.affiliation: Department of Developmental Biology and Cancer Research, The Institute for Medical Research Israel-Canada, Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel.
authors.forename: Seth J
authors.initials: SJ
authors.lastname: Salpeter
authors.forename: Agnes
authors.initials: A
authors.lastname: Klochendler
authors.forename: Noa
authors.initials: N
authors.lastname: Weinberg-Corem
authors.forename: Shay
authors.initials: S
authors.lastname: Porat
authors.forename: Zvi
authors.initials: Z
authors.lastname: Granot
authors.forename: A M James
authors.initials: AM
authors.lastname: Shapiro
authors.forename: Mark A
authors.initials: MA
authors.lastname: Magnuson
authors.forename: Amir
authors.initials: A
authors.lastname: Eden
authors.forename: Joseph
authors.initials: J
authors.lastname: Grimsby
authors.forename: Benjamin
authors.initials: B
authors.lastname: Glaser
authors.forename: Yuval
authors.initials: Y
authors.lastname: Dor
mesh_terms: D000818:Animals; D002120:Calcium Channel Agonists / Q000494:pharmacology; D015220:Calcium Channels / Q000378:metabolism*; D002453:Cell Cycle; D002460:Cell Line; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D049109:Cell Proliferation; D056742:Cyclin D2 / Q000235:genetics / Q000378:metabolism*; D003921:Diabetes Mellitus, Experimental / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D005947:Glucose / Q000378:metabolism*; D006019:Glycolysis / Q000187:drug effects; D006801:Humans; D007515:Islets of Langerhans / Q000166:cytology / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D008822:Mice, Transgenic; D009924:Organ Culture Techniques; D012333:RNA, Messenger / Q000378:metabolism
chemical_list: C080336:CCND2 protein, human; D002120:Calcium Channel Agonists; D015220:Calcium Channels; C486196:Ccnd2 protein, mouse; D056742:Cyclin D2; D004791:Enzyme Inhibitors; D012333:RNA, Messenger; D005947:Glucose