The role of β cell glucagon-like peptide-1 signaling in glucose regulation and response to diabetes drugs.
Glucagon-like peptide-1 (GLP-1), an insulinotropic gut peptide released after eating, is essential for normal glucose tolerance (GT). To determine whether this effect is mediated directly by GLP-1 receptors (GLP1R) on islet β cells, we developed mice with β cell-specific knockdown of Glp1r. β cell Glp1r knockdown mice had impaired GT after intraperitoneal (i.p.) glucose and did not secrete insulin in response to i.p. or intravenous GLP-1. However, they had normal GT after oral glucose, a response that was impaired by a GLP1R antagonist. β cell Glp1r knockdown mice had blunted responses to a GLP1R agonist but intact glucose lowering with a dipeptidylpeptidase 4 (DPP-4) inhibitor. Thus, in mice, β cell Glp1rs are required to respond to hyperglycemia and exogenous GLP-1, but other factors compensate for reduced GLP-1 action during meals. These results support a role for extraislet GLP1R in oral glucose tolerance and paracrine regulation of β cells by islet GLP-1.
Smith, EP; An, Z; Wagner, C; Lewis, AG; Cohen, EB; Li, B; Mahbod, P; Sandoval, D; Perez-Tilve, D; Tamarina, N; Philipson, LH; Stoffers, DA; Seeley, RJ; D'Alessio, DA
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