{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T18:20:25Z","timestamp":1788546025282,"version":"build-2803163510"},"reference-count":55,"publisher":"Bioscientifica","issue":"2","license":[{"start":{"date-parts":[[2026,2,18]],"date-time":"2026-02-18T00:00:00Z","timestamp":1771372800000},"content-version":"vor","delay-in-days":1253,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["journals.bioscientifica.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2022,11,1]]},"abstract":"<jats:p>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 &amp;lt; 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 &amp;lt; 0.05) the onset of hyperglycaemia. The treatments reduced (P &amp;lt; 0.05\u2013P &amp;lt; 0.001) circulating and pancreatic glucagon, whilst desHis1Pro4Glu9(Lys12PAL)-glucagon also substantially increased (P &amp;lt; 0.001) pancreatic insulin stores. Oral glucose tolerance was appreciably improved (P &amp;lt; 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 &amp;lt; 0.05\u2013P &amp;lt; 0.01) locomotor activity and increases (P &amp;lt; 0.001) in energy expenditure and respiratory exchange ratio in both treatment groups. In addition, desHis1Pro4Glu9-glucagon increased (P &amp;lt; 0.01\u2013P &amp;lt; 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.<\/jats:p>","DOI":"10.1530\/joe-22-0106","type":"journal-article","created":{"date-parts":[[2022,8,25]],"date-time":"2022-08-25T07:52:08Z","timestamp":1661413928000},"page":"91-101","update-policy":"https:\/\/doi.org\/10.1530\/crossmarkpolicy-5","source":"Crossref","is-referenced-by-count":8,"title":["Sustained glucagon receptor antagonism in insulin-deficient high-fat-fed mice"],"prefix":"10.1530","volume":"255","author":[{"given":"Ryan A","family":"Lafferty","sequence":"first","affiliation":[{"name":"Biomedical Sciences Research Institute 1","department":["Centre for Diabetes, Ulster University, Coleraine, Northern Ireland, UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura M","family":"McShane","sequence":"additional","affiliation":[{"name":"Biomedical Sciences Research 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