Absence of Glucagon and Insulin Action Reveals a Role for the Glucagon-like Peptide-1 Receptor in Endogenous Glucose Production

The absence of insulin results in oscillating hyperglycemia and ketoacidosis in type 1 diabetes mellitus. Remarkably, mice genetically deficient in the glucagon receptor ( Gcgr ) are refractory to the pathophysiological symptoms of insulin deficiency, and therefore, studies interrogating this unique model may uncover metabolic regulatory mechanisms that are independent of insulin. A significant feature of Gcgr null mice is the high circulating concentrations of glucagon-like peptide-1 (GLP-1). Hence, the objective of this report was to investigate potential non-insulinotropic roles of GLP-1 in mice where GCGR signaling is inactivated. For these studies, pancreatic β cells were chemically destroyed by streptozotocin (STZ) in Gcgr -/- : Glp-1r -/-mice and in Glp-1r -/- animals that were subsequently treated with a high-affinity GCGR antagonist antibody that recapitulates the physiological state of Gcgr ablation. Loss of GLP-1 action substantially worsened both non-fasting glucose concentrations and glucose tolerance in mice deficient in, and undergoing pharmacological inhibition of, the GCGR. Further, lack of the Glp-1r in STZ-treated Gcgr -/- mice elevated rates of endogenous glucose production, likely accounting for the differences in glucose homeostasis. These results support the emerging hypothesis that non-β cell actions of GLP-1 analogs may improve metabolic control in patients suffering from insulinopenic diabetes. and DKO mice showed DKO animals have a higher rate of EGP compared to Gcgr -/- mice (basal glycolytic rates were similar between the groups). These results agree with data showing GLP-1 infusion in fasted humans decreases EGP (42) and with studies in Glp-1r -/- mice displaying impaired suppression of EGP and liver glycogen accumulation during hyperinsulinemic-euglycemic clamp experiments (32). Based on data from our experiments shown here, we propose the loss of GLP-1R-dependent EGP suppression in insulin-deficient DKO mice likely accounts for differences in glycemic control observed in the DKO animals versus the Gcgr single knock-out mice. Further work to determine the key GLP-1R-expressing tissue(s) that regulates whole body EGP is warranted; other studies have demonstrated that activation of the GLP-1R in the CNS reduces hepatic glucose output (43). It remains unclear whether GLP-1R-expressing vagal afferents from the enteric system initiate CNS-driven effects on EGP. Conditional deletion of the Glp-1r in the peripheral nervous system and in regions such as the hypothalamic arcuate nucleus should be explored to better understand the suppressive role of the GLP-1R on EGP. Studies using the Gcgr -/- model herein demonstrate a non-insulin dependent role of the GLP-1R in controlling EGP. These results suggest that, in addition to the established ability of GLP-1 analogs to suppress glucagon secretion, GLP-1R activation in the state of insulin deficiency may improve overall glucose homeostasis. Early proof-of-concept trials show adjunctive treatment with the GLP-1 mimetics, liraglutide and exenatide, confers some efficacy in type diabetic While it is unclear whether antagonist