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Role of Phosphatidylinositol 3-Kinase in the ß-Cell: Interactions with Glucagon-Like Peptide-1

Departments of Physiology (L.-X.L., D.S.A., G.Y.O., P.H.B., P.L.B.) and Medicine (G.Y.O., P.H.B., P.L.B.), and Heart and Stroke/Richard Lewar Centre of Excellence (G.Y.O., P.H.B.), University of Toronto, Toronto, Ontario, Canada M5S 1A8; Department of Experimental Medical Science (P.E.M.), Lund University, S-221 84 Lund, Sweden; and Oxford Centre for Diabetes, Endocrinology, and Metabolism (P.E.M.), Oxford OX3 7LJ, United Kingdom

Address all correspondence and requests for reprints to: Dr. Patricia Brubaker, Room 3366 Medical Sciences Building, University of Toronto, Toronto, Ontario, Canada M5S 1A8. E-mail: p.brubaker{at}utoronto.ca.

Glucagon-like peptide-1 (GLP-1) increases ß-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-K is known to be activated by G_ß. Therefore, the role of PI3-K in the chronic effects of GLP-1 on the ß-cell was investigated using PI3-K 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 ß-cells with small interfering RNA for PI3-K similarly decreased glucose-stimulated insulin secretion (P < 0.01) and increased insulin content. Basal values for ß-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-K 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 ß-cell mass. These studies reveal a new role for PI3-K as a positive regulator of insulin secretion, and reinforce the importance of GLP-1 for the maintenance of normal ß-cell function.

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