Identification and Characterization of GLP-1 Receptor–Expressing Cells Using a New Transgenic Mouse Model

Glucagon-like peptide-1 (GLP-1) is an intestinal hormone with widespread actions on metabolism. Therapies based on GLP-1 are highly effective because they increase glucose-dependent insulin secretion in people with type 2 diabetes, but many reports suggest that GLP-1 has additional beneficial, or in some cases potentially dangerous, actions on other tissues, including the heart, vasculature, exocrine pancreas, liver and central nervous system. Identifying which tissues express the GLP-1 receptor (GLP1R) is critical for the development of GLP-1 based therapies. Our objective was to identify and characterise the targets of GLP-1 in mice, using a method independent of GLP1R antibodies. Using newly-generated glp1r-cre mice crossed with fluorescent reporter strains, we show that major sites of glp1r expression include pancreatic β and δ-cells, vascular smooth muscle, cardiac atrium, gastric antrum/pylorus, enteric neurones and vagal and dorsal root ganglia. In the central nervous sytem, glp1r-fluorescent cells were abundant in the area postrema, arcuate nucleus, paraventricular nucleus and ventromedial hypothalamus. Sporadic glp1r-fluorescent cells were found in pancreatic ducts. No glp1r-fluorescence was observed in ventricular cardiomyocytes. Glp1r-positive enteric and vagal neurons were activated by GLP-1, and may contribute to intestinal and central responses to locally-released GLP-1, such as regulation of intestinal secretomotor activity and appetite.