Metabolic effects of combined glucagon receptor antagonism and glucagon-like peptide-1 receptor agonism in high fat fed mice

Ablation of glucagon receptor (GCGR) signalling is a potential treatment option for diabetes, whilst glucagon-like peptide-1 (GLP-1) receptor agonists are clinically approved for both obesity and diabetes. There is a suggestion that GCGR blockade enhances GLP-1 secretion and action, whilst GLP-1 receptor activation is known to inhibit glucagon release, implying potential for positive interactions between both therapeutic avenues. The present study has examined the ability of sustained GCGR antagonism, using desHis ¹Pro ⁴Glu ⁹-glucagon, to augment the established benefits of the GLP-1 mimetic, exendin-4, in high fat fed (HFF) mice. Twice-daily injection of desHis ¹Pro ⁴Glu ⁹-glucagon, exendin-4 or a combination of both peptides to groups of HFF mice for 10 days had no impact on body weight or energy intake. Circulating blood glucose and glucagon concentrations were significantly (P < 0.05–0.01) decreased by all treatment regimens, with plasma insulin levels elevated (P < 0.001) when compared to lean control mice. Intraperitoneal and oral glucose tolerance were improved (P < 0.05–0.01) by all treatments, despite lack of enhanced glucose-stimulated insulin secretion. Following exogenous glucagon administration, all HFF treatment groups displayed reduced (P < 0.05–0.001) glucose and insulin levels compared to HFF saline controls, although peripheral insulin sensitivity was largely unchanged across all animals. Interestingly, all treatments had tendency to increase pancreatic insulin content with pancreatic glucagon content significantly elevated (P < 0.05) by all interventions. These studies highlight the capacity of peptide-based GCGR inhibition, or GLP-1 receptor activation, to significantly improve metabolism in HFF mice but suggest no obvious additive benefits of combined therapy.