[PDF][PDF] The role of β cell glucagon-like peptide-1 signaling in glucose regulation and response to diabetes drugs

EP Smith, Z An, C Wagner, AG Lewis, EB Cohen, B Li… - Cell metabolism, 2014 - cell.com
EP Smith, Z An, C Wagner, AG Lewis, EB Cohen, B Li, P Mahbod, D Sandoval…
Cell metabolism, 2014cell.com
Summary 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 (ip) glucose and did not secrete insulin in response to ip or intravenous GLP-
1. However, they had normal GT after oral glucose, a response that was impaired by a …
Summary
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.
cell.com