Sustained glucagon receptor antagonism in insulin deficient high fat fed mice

Ryan Lafferty, Ulster University, Zara Franklin, Peter Flatt, Ulster University, Nigel Irwin*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


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.
Original languageEnglish
Pages (from-to)91-101
Number of pages11
JournalThe Journal of endocrinology
Early online date25 Aug 2022
Publication statusPublished - 14 Sept 2022

Bibliographical note

This work was supported by an Invest Northern Ireland Proof-of-Concept grant (PoC106), a Department for the Economy, Northern Ireland PhD studentship and Ulster University Selective Research Funding

Data Availability Statement

The authors declare that the data supporting the findings of this study are available within the article. Any additional raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.


  • glucagon
  • glucose homeostasis
  • insulin sensitivity
  • high fat fed mice
  • streptozotocin


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