Tolerance develops toward GLP-1 receptor agonists' glucose-lowering effect in mice.

Glucagon-like peptide 1 (GLP-1) receptor agonists are popular antidiabetic drugs with potent glucose-lowering effects and low risk of hypoglycemia. Animal experiments and human data indicate that tolerance develops toward at least some of their effects, e.g., gastric motility. Whether tolerance develops toward the glucose-lowering effect of GLP-1 receptor agonists in mice has never been formally tested. The hypothesis of tolerance development in mice will be reported in this study. The direct glucose-lowering effect of the GLP-1 receptor agonists was measured in non-fasted mice and with intraperitoneal glucose tolerance test. Exenatide (10 μg/kg) and liraglutide (600 μg/kg) both substantially lost efficacy during the 18-day treatment as compared to the acute effect. We conclude that our results demonstrate development of tolerance toward GLP-1 receptor agonists' glucose-lowering effect in mice.