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.
Bibliographical noteFunding Information:
This work was supported by an Invest Northern Ireland Proof-of-Concept grant, a Department for the Economy , Northern Ireland PhD studentship and Ulster University Selective Research Funding.
This work was supported by an Invest Northern Ireland Proof-of-Concept grant, a Department for the Economy, Northern Ireland PhD studentship and Ulster University Selective Research Funding.
© 2022 The Authors
- Glucagon-like peptide-1 (GLP-1)
- Glucose homeostasis
- High fat fed mice
- Insulin secretion
- Insulin sensitivity