AIMS/HYPOTHESIS: Adult beta cells have a diminished ability to proliferate. Phosphatase and tensin homologue (PTEN) is a lipid phosphatase that antagonises the function of the mitogenic phosphatidylinositol 3-kinase (PI3K) pathway. The objective of this study was to understand the role of PTEN and PI3K signalling in the maintenance of beta cells postnatally. METHODS: We developed a Pten (lox/lox); Rosa26 (lacZ); RIP-CreER (+) model that permitted us to induce Pten deletion by treatment with tamoxifen in mature animals. We evaluated islet mass and function as well as beta cell proliferation in 3- and 12-month-old mice treated with tamoxifen (Pten deleted) vs mice treated with vehicle (Pten control). RESULTS: Deletion of Pten in juvenile (3-month-old) beta cells significantly induced their proliferation and increased islet mass. The expansion of islet mass occurred concomitantly with the enhanced ability of the Pten-deleted mice to maintain euglycaemia in response to streptozotocin treatment. In older mice (>12 months of age), deletion of Pten similarly increased islet mass and beta cell proliferation. This novel finding suggests that PTEN-regulated mechanisms may override the age-onset diminished ability of beta cells to respond to mitogenic stimulation. We also found that proteins regulating G1/S cell-cycle transition, such as cyclin D1, cyclin D2, p27 and p16, were altered when PTEN was lost, suggesting that they may play a role in PTEN/PI3K-regulated beta cell proliferation in adult tissue. CONCLUSIONS/ INTERPRETATION: The signals regulated by the PTEN/PI3K pathway are important for postnatal maintenance of beta cells and regulation of their proliferation in adult tissues.
AIMS/HYPOTHESIS: Adult beta cells have a diminished ability to proliferate. Phosphatase and tensin homologue (PTEN) is a lipid phosphatase that antagonises the function of the mitogenic phosphatidylinositol 3-kinase (PI3K) pathway. The objective of this study was to understand the role of PTEN and PI3K signalling in the maintenance of beta cells postnatally. METHODS: We developed a Pten (lox/lox); Rosa26 (lacZ); RIP-CreER (+) model that permitted us to induce Pten deletion by treatment with tamoxifen in mature animals. We evaluated islet mass and function as well as beta cell proliferation in 3- and 12-month-old mice treated with tamoxifen (Pten deleted) vs mice treated with vehicle (Pten control). RESULTS: Deletion of Pten in juvenile (3-month-old) beta cells significantly induced their proliferation and increased islet mass. The expansion of islet mass occurred concomitantly with the enhanced ability of the Pten-deleted mice to maintain euglycaemia in response to streptozotocin treatment. In older mice (>12 months of age), deletion of Pten similarly increased islet mass and beta cell proliferation. This novel finding suggests that PTEN-regulated mechanisms may override the age-onset diminished ability of beta cells to respond to mitogenic stimulation. We also found that proteins regulating G1/S cell-cycle transition, such as cyclin D1, cyclin D2, p27 and p16, were altered when PTEN was lost, suggesting that they may play a role in PTEN/PI3K-regulated beta cell proliferation in adult tissue. CONCLUSIONS/ INTERPRETATION: The signals regulated by the PTEN/PI3K pathway are important for postnatal maintenance of beta cells and regulation of their proliferation in adult tissues.
Authors: A García-Ocaña; R C Vasavada; A Cebrian; V Reddy; K K Takane; J C López-Talavera; A F Stewart Journal: Diabetes Date: 2001-12 Impact factor: 9.461
Authors: R L Tuttle; N S Gill; W Pugh; J P Lee; B Koeberlein; E E Furth; K S Polonsky; A Naji; M J Birnbaum Journal: Nat Med Date: 2001-10 Impact factor: 53.440
Authors: M Pende; S C Kozma; M Jaquet; V Oorschot; R Burcelin; Y Le Marchand-Brustel; J Klumperman; B Thorens; G Thomas Journal: Nature Date: 2000 Dec 21-28 Impact factor: 49.962
Authors: N Kubota; K Tobe; Y Terauchi; K Eto; T Yamauchi; R Suzuki; Y Tsubamoto; K Komeda; R Nakano; H Miki; S Satoh; H Sekihara; S Sciacchitano; M Lesniak; S Aizawa; R Nagai; S Kimura; Y Akanuma; S I Taylor; T Kadowaki Journal: Diabetes Date: 2000-11 Impact factor: 9.461