The incretin peptides glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) stimulate insulin secretion in β-cells by binding to cognate receptors. The GIPR and GLP-1R are family B G-protein coupled receptors generally thought to mediate signaling through G-αs and generation of cAMP. However, the GLP-1R has also been reported to signal through alternative pathways beyond Gαs, and the relative contributions of Gαs vs. non-Gαs are unknown. The GLP-1R is essential for basal levels of cAMP and normal β-cell tone. We hypothesized that elimination of Gαs would render mouse islets insensitive to GLP-1R agonists. Induction of β-cell specific Gnas knockout with tamoxifen inducible cre caused a >90% reduction in Gαs mRNA in purified β-cells (Gnasβcell-/-). Perifusion of control and knockout islets demonstrated reduced glucose-stimulated insulin secretion, but persistence of an insulin response to GLP-1R agonists that was ∼40% of control. Similarly, insulin secretion in response to either GIP or glucagon was only partially reduced in Gαs knockout islets. A Gq inhibitor partially reduced insulin secretion in control islets, but abolished GLP-1 stimulated insulin secretion in Gnasβcell-/- islets. These results demonstrate that the incretins can signal through both Gαs and non-Gαs mechanisms. Interestingly, Gnasβcell-/- mice were severely hyperglycemic (>400 mg/dl) and had no reduction of glycemia in response to GLP-1R or GIPR agonists. Thus, non-Gαs signaling by either GLP-1R or GIPR is unable to stimulate sufficient insulin secretion to maintain euglycemia in vivo.
M. Capozzi: None. S.M. Gray: None. P. Emmerson: None. F.S. Willard: None. K. Sloop: None. D. D’Alessio: Advisory Panel; Self; Eli Lilly and Company. Consultant; Self; Intarcia Therapeutics. Research Support; Self; Ansh Labs, Eli Lilly and Company, Merck Sharp & Dohme Corp. Other Relationship; Self; Novo Nordisk A/S. J. Campbell: Research Support; Self; Eli Lilly and Company, Novo Nordisk Inc. Speaker’s Bureau; Self; Merck Sharp & Dohme Corp.
American Diabetes Association (1-17-JDF-074 to J.C.); National Institutes of Health (R01DK123075, F32DK116542)