title: Insulin secretion induced by glucose-dependent insulinotropic polypeptide requires phosphatidylinositol 3-kinase γ in rodent and human β-cells.
abstract: PI3Kγ, a G-protein-coupled type 1B phosphoinositol 3-kinase, exhibits a basal glucose-independent activity in β-cells and can be activated by the glucose-dependent insulinotropic polypeptide (GIP). We therefore investigated the role of the PI3Kγ catalytic subunit (p110γ) in insulin secretion and β-cell exocytosis stimulated by GIP. We inhibited p110γ with AS604850 (1 μmol/liter) or knocked it down using an shRNA adenovirus or siRNA duplex in mouse and human islets and β-cells. Inhibition of PI3Kγ blunted the exocytotic and insulinotropic response to GIP receptor activation, whereas responses to the glucagon-like peptide-1 or the glucagon-like peptide-1 receptor agonist exendin-4 were unchanged. Downstream, we find that GIP, much like glucose stimulation, activates the small GTPase protein Rac1 to induce actin remodeling. Inhibition of PI3Kγ blocked these effects of GIP. Although exendin-4 could also stimulate actin remodeling, this was not prevented by p110γ inhibition. Finally, forced actin depolymerization with latrunculin B restored the exocytotic and secretory responses to GIP during PI3Kγ inhibition, demonstrating that the loss of GIP-induced actin depolymerization was indeed limiting insulin exocytosis.
authors.affiliation: Department of Pharmacology, and the Alberta Diabetes Institute, University of Alberta, Edmonton, Alberta T6G 2E1, Canada.
authors.forename: Jelena
authors.initials: J
authors.lastname: Kolic
authors.affiliation: Department of Pharmacology, and the Alberta Diabetes Institute, University of Alberta, Edmonton, Alberta T6G 2E1, Canada.
authors.forename: Aliya F
authors.initials: AF
authors.lastname: Spigelman
authors.affiliation: Department of Pharmacology, and the Alberta Diabetes Institute, University of Alberta, Edmonton, Alberta T6G 2E1, Canada.
authors.forename: Alannah M
authors.initials: AM
authors.lastname: Smith
authors.affiliation: Department of Pharmacology, and the Alberta Diabetes Institute, University of Alberta, Edmonton, Alberta T6G 2E1, Canada.
authors.forename: Jocelyn E
authors.initials: JE
authors.lastname: Manning Fox
authors.affiliation: Department of Pharmacology, and the Alberta Diabetes Institute, University of Alberta, Edmonton, Alberta T6G 2E1, Canada. Electronic address: pmacdonald@ualberta.ca.
authors.forename: Patrick E
authors.initials: PE
authors.lastname: MacDonald
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D058544:Class Ib Phosphatidylinositol 3-Kinase / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism; D004149:Dioxoles / Q000737:chemistry; D004594:Electrophysiology; D005089:Exocytosis; D005749:Gastric Inhibitory Polypeptide / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic; D005947:Glucose / Q000378:metabolism*; D006801:Humans; D020128:Inhibitory Concentration 50; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism; D007515:Islets of Langerhans / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D009479:Neuropeptides / Q000378:metabolism; D017434:Protein Structure, Tertiary; D045162:Thiazolidinediones / Q000737:chemistry; D020830:rac1 GTP-Binding Protein / Q000378:metabolism
chemical_list: C505145:5-(2,2-difluorobenzo(1,3)dioxol-5-ylmethylene)thiazolidine-2,4-dione; D000199:Actins; D004149:Dioxoles; D007328:Insulin; D009479:Neuropeptides; C484602:Rac1 protein, mouse; D045162:Thiazolidinediones; D005749:Gastric Inhibitory Polypeptide; D058544:Class Ib Phosphatidylinositol 3-Kinase; D020830:rac1 GTP-Binding Protein; D005947:Glucose
keywords: Actin; Exocytosis; Insulin; Pancreatic Islet; Phosphatidylinositide 3-Kinase (PI 3-Kinase); Ras-related C3 Botulinum Toxin Substrate 1 (Rac1); Type 2 Diabetes