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 desHis1Pro4Glu9-glucagon, to augment the established benefits of the
GLP-1 mimetic,
exendin-4, in high fat fed (HFF) mice. Twice-daily injection of desHis1Pro4Glu9-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.