Role of phosphatidylinositol 3-kinasegamma in the beta-cell: interactions with glucagon-like peptide-1

Endocrinology. 2006 Jul;147(7):3318-25. doi: 10.1210/en.2006-0155. Epub 2006 Mar 30.


Glucagon-like peptide-1 (GLP-1) increases beta-cell function and growth through protein kinase A- and phosphatidylinositol-3-kinase (PI3-K)/protein kinase B, respectively. GLP-1 acts via a G protein-coupled receptor, and PI3-Kgamma is known to be activated by G(betagamma.) Therefore, the role of PI3-Kgamma in the chronic effects of GLP-1 on the beta-cell was investigated using PI3-Kgamma knockout (KO) mice treated with the GLP-1 receptor agonist, exendin-4 (Ex4; 1 nmol/kg sc every 24 h for 14 d). In vivo, glucose and insulin responses were similar in PBS- and Ex4-treated KO and wild-type (WT) mice. However, glucose-stimulated insulin secretion was markedly impaired in islets from PBS-KO mice (P < 0.05), and this was partially normalized by chronic Ex4 treatment (P < 0.05). In contrast, insulin content was increased in PBS-KO islets, and this was paradoxically decreased by Ex4 treatment, compared with the stimulatory effect of Ex4 on WT islets (P < 0.05-0.01). Transfection of INS-1E beta-cells with small interfering RNA for PI3-Kgamma similarly decreased glucose-stimulated insulin secretion (P < 0.01) and increased insulin content. Basal values for beta-cell mass, islet number and proliferation, glucose transporter 2, glucokinase, and insulin receptor substrate-2 were increased in PBS-KO mice (P < 0.05-0.001) and, although they were increased by Ex4 treatment of WT animals (P < 0.05), they were decreased in Ex4-KO mice (P < 0.05-0.01). These findings indicate that PI3-Kgamma deficiency impairs insulin secretion, resulting in compensatory islet growth to maintain normoglycemia. Chronic Ex4 treatment normalizes the secretory defect, thereby relieving the pressure for expansion of beta-cell mass. These studies reveal a new role for PI3-Kgamma as a positive regulator of insulin secretion, and reinforce the importance of GLP-1 for the maintenance of normal beta-cell function.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Class Ib Phosphatidylinositol 3-Kinase
  • GTP-Binding Protein beta Subunits / metabolism
  • GTP-Binding Protein gamma Subunits / metabolism
  • Glucagon-Like Peptide 1 / metabolism
  • Glucagon-Like Peptide 1 / physiology*
  • Glucose / metabolism
  • Insulin / metabolism
  • Insulin-Secreting Cells / metabolism*
  • Isoenzymes / metabolism
  • Isoenzymes / physiology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Pancreas / metabolism
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphatidylinositol 3-Kinases / physiology*
  • Protein Binding
  • RNA Interference


  • G-protein Beta gamma
  • GTP-Binding Protein beta Subunits
  • GTP-Binding Protein gamma Subunits
  • Insulin
  • Isoenzymes
  • Glucagon-Like Peptide 1
  • Phosphatidylinositol 3-Kinases
  • Class Ib Phosphatidylinositol 3-Kinase
  • Pik3cg protein, mouse
  • Glucose