Sustained glucagon receptor antagonism in insulin-deficient high-fat-fed mice

Abstract

Discerning modification to the amino acid sequence of native glucagon can generate specific glucagon receptor (GCGR) antagonists, that include desHis ¹Pro ⁴Glu ⁹-glucagon and the acylated form desHis ¹Pro ⁴Glu ⁹(Lys ¹²PAL)-glucagon. In the current study, we have evaluated the metabolic benefits of once-daily injection of these peptide-based GCGR antagonists for 18 days in insulin-resistant high-fat-fed (HFF) mice with streptozotocin (STZ)-induced insulin deficiency, namely HFF-STZ mice. Administration of desHis ¹Pro ⁴Glu ⁹-glucagon moderately ( P < 0.05) decreased STZ-induced elevations of food intake. Body weight was not different between groups of HFF-STZ mice and both treatment interventions delayed ( P < 0.05) the onset of hyperglycaemia. The treatments reduced ( P < 0.05– P < 0.001) circulating and pancreatic glucagon, whilst desHis ¹Pro ⁴Glu ⁹(Lys ¹²PAL)-glucagon also substantially increased ( P < 0.001) pancreatic insulin stores. Oral glucose tolerance was appreciably improved ( P < 0.05) by both antagonists, despite the lack of augmentation of glucose-stimulated insulin release. Interestingly, positive effects on i.p. glucose tolerance were less obvious suggesting important beneficial effects on gut function. Metabolic benefits were accompanied by decreased ( P < 0.05– P < 0.01) locomotor activity and increases ( P < 0.001) in energy expenditure and respiratory exchange ratio in both treatment groups. In addition, desHis ¹Pro ⁴Glu ⁹-glucagon increased ( P < 0.01 –P < 0.001) O ₂ consumption and CO ₂ production. Together, these data provide further evidence that peptidic GCGR antagonists are effective treatment options for obesity-driven forms of diabetes, even when accompanied by insulin deficiency.