AIMS/HYPOTHESIS: Glucagon-like peptide-2 (GLP-2) is a gut hormone regulating intestinal growth and nutrient absorption. Recently, GLP-2 has been reported to stimulate glucagon secretion in healthy humans. We sought to clarify the mechanism and physiological significance of this endocrine effect.

MATERIALS AND METHODS: The expression of the GLP-2 receptor gene, Glpr2, and the localisation of the protein were evaluated by real-time PCR on cDNA from isolated rat islets and by immunohistochemistry in rat and human pancreas. The glucagon, insulin and somatostatin responses to 0.1, 1 and 10 nmol/l GLP-2 and to GLP-1 and GLP-2 given simultaneously were studied in the isolated perfused rat pancreas.

RESULTS: Expression of Glp2r transcript was confirmed by PCR. In both human and rat pancreas, GLP-2r immunoreactivity was colocalised with proglucagon. GLP-2 at 10 nmol/l increased glucagon secretion significantly from a pre-infusion level of 0.314 +/- 0.07 to 0.508 +/- 0.09 pmol/min (p < 0.0005), whereas lower GLP-2 concentrations were ineffective. Neither insulin nor somatostatin output was influenced. During simultaneous administration of GLP-1 and GLP-2, net glucagon release was no longer reduced by 0.1, 1 or 10 nmol/l GLP-1, which, when given alone, inhibited glucagon secretion by 25.0 +/- 9.9, 46.2 +/- 4.8, and 44.1 +/- 2.9%, respectively.

CONCLUSIONS/INTERPRETATION: Our results suggest that GLP-2 stimulates glucagon secretion through GLP-2r present on the alpha cell in rats. In the presence of GLP-2, the glucagonostatic effect of GLP-1, normally co-secreted with GLP-2, is markedly inhibited. Based on our analogous immunohistochemical findings in human pancreas, this mechanism also applies in all likelihood to humans. However, further in vivo studies are required to assess the physiological significance of the glucagonotropic action of GLP-2 in humans.