IDENTIFICATION OF GLUCAGON-LIKE PEPTIDE-1 (GLP-1) ACTIONS ESSENTIAL FOR GLUCOSE-HOMEOSTASIS IN MICE WITH DISRUPTION OF GLP-1 RECEPTOR SIGNALING

Glucagon-like peptide-1 (GLP-1) acts to control blood glucose via mult iple mechanisms, including regulation of insulin and glucagon secretio n, gastric emptying, satiety, and peripheral insulin sensitivity. Howe ver, 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 con trast, GLP-1 signaling is not required for normal control of fasting a nd postabsorptive glucagon levels, and no significant changes were det ected in the tissue content of pancreatic and intestinal proglucagon m RNA, glucagon-like immunoreactivity, or GLP-1 in GLP-1R -/- or +/- mic e. Despite the demonstration that GLP-1 stimulates proinsulin gene tra nscription, pancreatic insulin mRNA transcripts were similar in wild-t ype and GLP-1R -/- mice. Furthermore, despite suggestions that GLP-1 r egulates peripheral glucose disposal, whole-body glucose utilization w as similar in wild-type and GLP-1R -/- mice under both basal and hyper insulinemic conditions. These observations demonstrate that of the num erous physiological activities ascribed to GLP-1, only the incretin ef fect on pancreatic beta-cells appears essential for regulation of gluc ose homeostasis in vivo.