Abstract
Discerning modification to the amino acid sequence of native glucagon can generate specific glucagon receptor (GCGR) antagonists, that include desHis1Pro4Glu9-glucagon and the acylated form desHis1Pro4Glu9(Lys12PAL)-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 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-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, 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 forms of diabetes, even when accompanied by insulin deficiency.
Original language | English |
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Pages (from-to) | 91-101 |
Number of pages | 11 |
Journal | Journal of Endrocrinology |
Volume | 255 |
Issue number | 2 |
Early online date | 14 Sept 2022 |
DOIs | |
Publication status | Published (in print/issue) - 1 Nov 2022 |
Bibliographical note
Funding Information: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.
Publisher Copyright:
© 2022 The authors Published by Bioscientifica Ltd.
Keywords
- glucagon
- glucose homeostasis
- insulin sensitivity
- high fat fed mice
- streptozotocin
- Endocrinology, Diabetes and Metabolism
- Endocrinology