title: Control of beta cell function and proliferation in mice stimulated by small-molecule glucokinase activator under various conditions.
abstract: OBJECTIVE
  We investigated changes in the expression of genes involved in beta cell function and proliferation in mouse islets stimulated with glucokinase activator (GKA) in order to elucidate the mechanisms by which GKA stimulates beta cell function and proliferation.
  
  
  METHODS
  Islets isolated from mice were used to investigate changes in the expression of genes related to beta cell function and proliferation stimulated by GKA. In addition, Irs2 knockout (Irs2                            (-/-)) mice on a high-fat diet or a high-fat diet containing GKA were used to investigate the effects of GKA on beta cell proliferation in vivo.
  
  
  RESULTS
  In wild-type mice, Irs2 and Pdx1 expression was increased by GKA. In Irs2                            (-/-) mice, GKA administration increased the glucose-stimulated secretion of insulin and Pdx1 expression, but not beta cell proliferation. It was particularly noteworthy that oxidative stress inhibited the upregulation of the Irs2 and Pdx1 genes induced by GKA. Moreover, whereas neither GKA alone nor exendin-4 alone upregulated the expression of Irs2 and Pdx1 in the islets of db/db mice, prior administration of exendin-4 to the mice caused GKA to increase the expression of these genes.
  
  
  CONCLUSIONS
  GKA-stimulated IRS2 production affected beta cell proliferation but not beta cell function. Oxidative stress diminished the effects of GKA on the changes in expression of genes involved in beta cell function and proliferation. A combination of GKA and an incretin-related agent might therefore be effective in therapy.
authors.affiliation: Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama City University, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Nakamura
authors.forename: Y
authors.initials: Y
authors.lastname: Togashi
authors.forename: K
authors.initials: K
authors.lastname: Orime
authors.forename: K
authors.initials: K
authors.lastname: Sato
authors.forename: J
authors.initials: J
authors.lastname: Shirakawa
authors.forename: M
authors.initials: M
authors.lastname: Ohsugi
authors.forename: N
authors.initials: N
authors.lastname: Kubota
authors.forename: T
authors.initials: T
authors.lastname: Kadowaki
authors.forename: Y
authors.initials: Y
authors.lastname: Terauchi
mesh_terms: D000818:Animals; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects*; D020536:Enzyme Activators / Q000494:pharmacology*; D005941:Glucokinase / Q000378:metabolism*; D007150:Immunohistochemistry; D055504:Insulin Receptor Substrate Proteins; D050417:Insulin-Secreting Cells / Q000166:cytology* / Q000187:drug effects*; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D018384:Oxidative Stress / Q000187:drug effects / Q000235:genetics
chemical_list: D020536:Enzyme Activators; D055504:Insulin Receptor Substrate Proteins; C526298:Irs2 protein, mouse; D005941:Glucokinase