The Role of β Cell Glucagon-like Peptide-1 Signaling in Glucose Regulation and Response to Diabetes Drugs

• Published in: Cell metabolism 2014-06, Vol.19 (6), p.1050-1057
• Main Authors: Smith, Eric P., An, Zhibo, Wagner, Constance, Lewis, Alfor G., Cohen, Eric B., Li, Bailing, Mahbod, Parinaz, Sandoval, Darleen, Perez-Tilve, Diego, Tamarina, Natalia, Philipson, Louis H., Stoffers, Doris A., Seeley, Randy J., D’Alessio, David A.
• Format: Article
• Language: English
• Subjects: Animals; Blood Glucose; Dipeptidyl Peptidase 4 - metabolism; Glucagon-Like Peptide 1 - agonists; Glucagon-Like Peptide 1 - metabolism; Glucagon-Like Peptide-1 Receptor; Glucose - metabolism; Glucose - pharmacology; Glucose Intolerance; Hyperglycemia - metabolism; Hypoglycemic Agents - pharmacology; Insulin - metabolism; Insulin Secretion; Insulin-Secreting Cells - metabolism; Mice; Mice, Knockout; Receptors, Glucagon - antagonists & inhibitors; Receptors, Glucagon - genetics; Receptors, Glucagon - metabolism; Signal Transduction; Tamoxifen - pharmacology
• ISSN: 1550-4131; 1932-7420
• DOI: 10.1016/j.cmet.2014.04.005

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. [Display omitted] •β cell Glp1rs are not necessary for normal oral glucose tolerance in lean mice•The incretin effect of GLP-1 is not mediated through an endocrine mechanism•β cell Glp1rs are required for normal responses to hyperglycemia and GLP1R agonists•DPP-4 inhibitors improve glucose tolerance through non-β cell Glp1r Glucagon-like peptide-1 (GLP-1) is an insulinotropic peptide essential for normal glucose tolerance. Through selective knockdown of Glp1r in islet β cells, Smith et al. demonstrate that the effects of GLP-1 on oral glucose tolerance do not depend on direct signaling through β cell GLP1R. These results support a neural/paracrine rather than endocrine mechanism of GLP-1 action.