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

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

Author information

1
Division of Endocrinology, Department of Internal Medicine, University of Cincinnati, Cincinnati, OH 45267, USA.
2
Department of Medicine, The Kovler Diabetes Center, University of Chicago, Chicago, IL 60637, USA.
3
Institute for Diabetes, Obesity and Metabolism and the Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.
4
Division of Endocrinology, Department of Internal Medicine, University of Cincinnati, Cincinnati, OH 45267, USA; Cincinnati Veterans Affairs Medical Center, Cincinnati, OH 45237, USA. Electronic address: dalessd@ucmail.uc.edu.

Abstract

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.

PMID:
24836562
PMCID:
PMC4109713
DOI:
10.1016/j.cmet.2014.04.005
[Indexed for MEDLINE]
Free PMC Article

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