title: Rb and p107 are required for alpha cell survival, beta cell cycle control and glucagon-like peptide-1 action.
abstract: OBJECTIVE
  Diabetes mellitus is characterised by beta cell loss and alpha cell expansion. Analogues of glucagon-like peptide-1 (GLP-1) are used therapeutically to antagonise these processes; thus, we hypothesised that the related cell cycle regulators retinoblastoma protein (Rb) and p107 were involved in GLP-1 action.
  
  
  METHODS
  We used small interfering RNA and adenoviruses to manipulate Rb and p107 expression in insulinoma and alpha-TC cell lines. In vivo we examined pancreas-specific Rb knockout, whole-body p107 knockout and Rb/p107 double-knockout mice.
  
  
  RESULTS
  Rb, but not p107, was downregulated in response to the GLP-1 analogue, exendin-4, in both alpha and beta cells. Intriguingly, this resulted in opposite outcomes of cell cycle arrest in alpha cells but proliferation in beta cells. Overexpression of Rb in alpha and beta cells abolished or attenuated the effects of exendin-4 supporting the important role of Rb in GLP-1 modulation of cell cycling. Similarly, in vivo, Rb, but not p107, deficiency was required for the beta cell proliferative response to exendin-4. Consistent with this finding, Rb, but not p107, was suppressed in islets from humans with diabetes, suggesting the importance of Rb regulation for the compensatory proliferation that occurs under insulin resistant conditions. Finally, while p107 alone did not have an essential role in islet homeostasis, when combined with Rb deletion, its absence potentiated apoptosis of both alpha and beta cells resulting in glucose intolerance and diminished islet mass with ageing.
  
  
  CONCLUSIONS
  We found a central role of Rb in the dual effects of GLP-1 in alpha and beta cells. Our findings highlight unique contributions of individual Rb family members to islet cell proliferation and survival.
authors.affiliation: Toronto General Research Institute, University Health Network, 101 College Street, MaRS Centre/TMDT, Room 10-363, Toronto, ON, M5G 1L7, Canada.
authors.forename: Erica P
authors.initials: EP
authors.lastname: Cai
authors.forename: Cynthia T
authors.initials: CT
authors.lastname: Luk
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Wu
authors.forename: Stephanie A
authors.initials: SA
authors.lastname: Schroer
authors.forename: Sally Yu
authors.initials: SY
authors.lastname: Shi
authors.forename: Tharini
authors.initials: T
authors.lastname: Sivasubramaniyam
authors.forename: Jara J
authors.initials: JJ
authors.lastname: Brunt
authors.forename: Eldad
authors.initials: E
authors.lastname: Zacksenhaus
authors.forename: Minna
authors.initials: M
authors.lastname: Woo
mesh_terms: D000818:Animals; D002453:Cell Cycle / Q000187:drug effects / Q000502:physiology*; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology*; D000077270:Exenatide; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism*; D050416:Glucagon-Secreting Cells / Q000187:drug effects / Q000378:metabolism*; D006706:Homeostasis / Q000187:drug effects / Q000502:physiology; D006801:Humans; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D010455:Peptides / Q000494:pharmacology; D016160:Retinoblastoma Protein / Q000235:genetics / Q000378:metabolism*; D050720:Retinoblastoma-Like Protein p107 / Q000235:genetics / Q000378:metabolism*; D014688:Venoms / Q000494:pharmacology
chemical_list: D010455:Peptides; D016160:Retinoblastoma Protein; D050720:Retinoblastoma-Like Protein p107; D014688:Venoms; D052216:Glucagon-Like Peptide 1; D000077270:Exenatide