Glucagon-like peptide-1 (GLP-1) acts to control blood glucose via multiple mechanisms; including regulation of insulin and glucagon secretion, gastric emptying, satiety, and peripheral insulin sensitivity. However, the relative importance of these actions for regulation of blood glucose remains unclear. We demonstrate here a gene dosage effect for the incretin action of GLP-1, as heterozygous GLP-1R +/- mice exhibit an abnormal glycemic response to oral glucose challenge in association with reduced circulating levels of glucose-stimulated insulin. In contrast, GLP-1 signaling is not required for normal control of fasting and postabsorp, five glucagon levels, and no significant changes were detected in the tissue content of pancreatic and intestinal proglucagon mRNA, glucagon-like immunoreactivity, or GLP-1 in GLP- 1R -/- or +/- mice. Despite the demonstration that GLP-1 stimulates proinsulin gene transcription, pancreatic insulin mRNA transcripts were similar in wild-type and (GLP-1R -/- mice. Furthermore, despite suggestions that GLP-1 regulates peripheral glucose disposal, whole-body glucose utilization was similar in wild-type and GLP-1R -/- mice under both basal and hyperinsulinemic conditions. These observations demonstrate that of the numerous physiological activities ascribed to GLP-I, only the incretin effect on pancreatic β-cells appears essential for regulation of glucose homeostasis in vivo.