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

Cell Metab. 2014 Jun 3;19(6):1050-7. doi: 10.1016/j.cmet.2014.04.005. Epub 2014 May 15.


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • 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


  • Blood Glucose
  • Glp1r protein, mouse
  • Glucagon-Like Peptide-1 Receptor
  • Hypoglycemic Agents
  • Insulin
  • Receptors, Glucagon
  • Tamoxifen
  • Glucagon-Like Peptide 1
  • Dipeptidyl Peptidase 4
  • Dpp4 protein, mouse
  • Glucose