Insulin Secretion Induced by Glucose-dependent Insulinotropic Polypeptide Requires PI3 Kinase-{gamma} in Rodent and Human {beta}-Cells [Cell Biology]

October 6th, 2014 by Kolic, J., Spigelman, A. F., Smith, A. M., Manning Fox, J. E., MacDonald, P. E.

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/l), 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, while responses to the glucagon-like peptide 1 (GLP-1) or the GLP-1 receptor agonist exendin-4 (Ex-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. While Ex-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.
  • Posted in Journal of Biological Chemistry, Publications
  • Comments Off on Insulin Secretion Induced by Glucose-dependent Insulinotropic Polypeptide Requires PI3 Kinase-{gamma} in Rodent and Human {beta}-Cells [Cell Biology]