Characterization of mice with a null mutation in the glucagon-like peptide-1 receptor gene

grantor: University of TorontoGlucagon-like peptide-1 (GLP-1) regulates blood glucose through stimulation of glucose-dependent insulin secretion, inhibition of gastric emptying, suppression of glucagon secretion, and the induction of satiety, as well as through potential actions on peripheral insulin sensitivity. We demonstrate here that the absence of GLP-1 signaling impairs the capacity of GLP-1R-/- mice to respond to agents associated with the induction of insulin resistance in vivo. Furthermore, despite reports that GLP-1 may influence peripheral insulin sensitivity, GLP-1R-/- mice were unresponsive to treatment with an insulin-sensitizing thiazolidinedione agent, suggesting GLP-1R-/- mice possess normal peripheral insulin sensitivity. Additionally, our studies show that GLP-1R+/- mice exhibit defective oral glucose tolerance in association with reduced glucose-stimulated insulin levels, supporting an essential role for GLP-1 in glucose homeostasis in vivo. Inhibition of DPP-IV using the chemical agent Pro-boroPro improved oral glucose tolerance in both wildtype and GLP-1R-/- mice, further implicating a role for this enzyme in incretin degradation in vivo. Additional studies undertaken here suggest that GLP-1R-/- mice exhibit an altered sensitivity to leptin, and furthermore, that disruption of GLP-1 signaling produces behavioural changes and perturbations in fluid homeostasis in vivo. Taken together, these studies further implicate a key role for GLP-1 not only in glucose homeostasis but also in the central regulation of behaviour and neuroendocrine function in vivo.M.Sc