title: Phosphatidylinositol 3-kinase suppresses glucose-stimulated insulin secretion by affecting post-cytosolic [Ca(2+)] elevation signals.
abstract: The role of phosphatidylinositol (PI) 3-kinase in the regulation of pancreatic beta-cell function was investigated. PI 3-kinase activity in p85 alpha regulatory subunit-deficient (p85 alpha(-/-)) islets was decreased to approximately 20% of that in wild-type controls. Insulin content and mass of rough endoplasmic reticula were decreased in beta-cells from p85 alpha(-/-) mice with increased insulin sensitivity. However, p85 alpha(-/-) beta-cells exhibited a marked increase in the insulin secretory response to higher concentrations of glucose. When PI 3-kinase in wild-type islets was suppressed by wortmannin or LY294002, the secretion was also substantially potentiated. Wortmannin's potentiating effect was not due to augmentation in glucose metabolism or cytosolic [Ca(2+)] elevation. Results of p85 alpha(-/-) islets and wortmannin-treated wild-type islets stimulated with diazoxide and KCl showed that inhibition of PI 3-kinase activity exerted its effect on secretion, at least in part, distal to a cytosolic [Ca(2+)] elevation. These results suggest that PI 3-kinase activity normally plays a crucial role in the suppression of glucose-stimulated insulin secretion.
authors.affiliation: Department of Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Eto
authors.forename: Tokuyuki
authors.initials: T
authors.lastname: Yamashita
authors.forename: Yoshiharu
authors.initials: Y
authors.lastname: Tsubamoto
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Terauchi
authors.forename: Kenzo
authors.initials: K
authors.lastname: Hirose
authors.forename: Naoto
authors.initials: N
authors.lastname: Kubota
authors.forename: Shigeo
authors.initials: S
authors.lastname: Yamashita
authors.forename: Junko
authors.initials: J
authors.lastname: Taka
authors.forename: Shinobu
authors.initials: S
authors.lastname: Satoh
authors.forename: Hisahiko
authors.initials: H
authors.lastname: Sekihara
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Tobe
authors.forename: Masamitsu
authors.initials: M
authors.lastname: Iino
authors.forename: Mitsuhiko
authors.initials: M
authors.lastname: Noda
authors.forename: Satoshi
authors.initials: S
authors.lastname: Kimura
authors.forename: Takashi
authors.initials: T
authors.lastname: Kadowaki
mesh_terms: D000730:Androstadienes; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002867:Chromones / Q000494:pharmacology; D003600:Cytosol / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000235:genetics / Q000648:ultrastructure; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005947:Glucose / Q000494:pharmacology*; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009025:Morpholines / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D021122:Protein Subunits; D000077191:Wortmannin
chemical_list: D000730:Androstadienes; D002867:Chromones; D004791:Enzyme Inhibitors; D007328:Insulin; D009025:Morpholines; D021122:Protein Subunits; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D019869:Phosphatidylinositol 3-Kinases; D005947:Glucose; D002118:Calcium; D000077191:Wortmannin