Sustained glucagon receptor antagonism in insulin deficient high fat fed mice

Discerning modification to the amino acid sequence of native glu cagon can generate specific glucagon receptor (GCGR) antagonists, that include desH is1Pro4Glu9-glucagon
and the acylated form desHis1Pro4Glu9(Lys12PAL)-glucagon. In the current study, we have evaluated the metabolic benefits of once-daily injection of these peptidebased GCGR antagonists for 18 days in insulin-resistant high-fa t-fed (HFF) mice with streptozotocin (STZ)-induced insulin deficiency, namely HFF-STZ mice. Administration of desHis1Pro4Glu9-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 desHis1Pro4Glu9(Lys12PAL)-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-stimul ated insulin release. Interestingly, positive effects on i.p. glucose tolerance were l ess obvious suggesting important beneficial effects on gut function. Metabolic benefits w ere 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 gr oups. In addition, desHis1Pro4Glu9-glucagon increased (P < 0.01–P < 0.001) O2 consumption and CO2 production. Together, these data provide further evidence that peptidic GCGR antagonists are effective treatment options for obesity-driven f orms of diabetes, even when accompanied by insulin deficiency.