{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T14:20:51Z","timestamp":1784557251040,"version":"3.55.0"},"reference-count":56,"publisher":"Bioscientifica","issue":"3","content-domain":{"domain":["joe.bioscientifica.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2016,6]]},"abstract":"<jats:p>\n                    Ablation of glucagon receptor signaling represents a potential treatment option for type 2 diabetes (T2DM). Additionally, activation of glucose-dependent insulinotropic polypeptide (GIP) receptor signaling also holds therapeutic promise for T2DM. Therefore, this study examined both independent and combined metabolic actions of desHis\n                    <jats:sup>1<\/jats:sup>\n                    Pro\n                    <jats:sup>4<\/jats:sup>\n                    Glu\n                    <jats:sup>9<\/jats:sup>\n                    (Lys\n                    <jats:sup>12<\/jats:sup>\n                    PAL)-glucagon (glucagon receptor antagonist) and\n                    <jats:sc>d<\/jats:sc>\n                    -Ala\n                    <jats:sup>2<\/jats:sup>\n                    GIP (GIP receptor agonist) in diet-induced obese mice. Glucagon receptor binding has been linked to alpha-helical structure and desHis\n                    <jats:sup>1<\/jats:sup>\n                    Pro\n                    <jats:sup>4<\/jats:sup>\n                    Glu\n                    <jats:sup>9<\/jats:sup>\n                    (Lys\n                    <jats:sup>12<\/jats:sup>\n                    PAL)-glucagon displayed enhanced alpha-helical content compared with native glucagon. In clonal pancreatic BRIN-BD11 beta-cells, desHis\n                    <jats:sup>1<\/jats:sup>\n                    Pro\n                    <jats:sup>4<\/jats:sup>\n                    Glu\n                    <jats:sup>9<\/jats:sup>\n                    (Lys\n                    <jats:sup>12<\/jats:sup>\n                    PAL)-glucagon was devoid of any insulinotropic or cAMP-generating actions, and did not impede\n                    <jats:sc>d<\/jats:sc>\n                    -Ala\n                    <jats:sup>2<\/jats:sup>\n                    GIP-mediated (\n                    <jats:italic>P<\/jats:italic>\n                    &lt;0.01 to\n                    <jats:italic>P<\/jats:italic>\n                    &lt;0.001) effects on insulin and cAMP production. Twice-daily injection of desHis\n                    <jats:sup>1<\/jats:sup>\n                    Pro\n                    <jats:sup>4<\/jats:sup>\n                    Glu\n                    <jats:sup>9<\/jats:sup>\n                    (Lys\n                    <jats:sup>12<\/jats:sup>\n                    PAL)-glucagon or\n                    <jats:sc>d<\/jats:sc>\n                    -Ala\n                    <jats:sup>2<\/jats:sup>\n                    GIP alone, and in combination, in high-fat-fed mice failed to affect body weight or energy intake. Circulating blood glucose levels were significantly (\n                    <jats:italic>P<\/jats:italic>\n                    &lt;0.05 to\n                    <jats:italic>P<\/jats:italic>\n                    &lt;0.01) decreased by all treatments regimens, with plasma and pancreatic insulin elevated (\n                    <jats:italic>P<\/jats:italic>\n                    &lt;0.05 to\n                    <jats:italic>P<\/jats:italic>\n                    &lt;0.001) in all mice receiving\n                    <jats:sc>d<\/jats:sc>\n                    -Ala\n                    <jats:sup>2<\/jats:sup>\n                    GIP. Interestingly, plasma glucagon concentrations were decreased (\n                    <jats:italic>P<\/jats:italic>\n                    &lt;0.05) by sustained glucagon inhibition (day 28), but increased (\n                    <jats:italic>P<\/jats:italic>\n                    &lt;0.05) by\n                    <jats:sc>d<\/jats:sc>\n                    -Ala\n                    <jats:sup>2<\/jats:sup>\n                    GIP therapy, with a combined treatment resulting in glucagon concentration similar to saline controls. All treatments improved (\n                    <jats:italic>P<\/jats:italic>\n                    &lt;0.01) intraperitoneal and oral glucose tolerance, and peripheral insulin sensitivity.\n                    <jats:sc>d<\/jats:sc>\n                    -Ala\n                    <jats:sup>2<\/jats:sup>\n                    GIP-treated mice showed increased glucose-induced insulin secretion in response to intraperitoneal and oral glucose. Metabolic rate and ambulatory locomotor activity were increased (\n                    <jats:italic>P<\/jats:italic>\n                    &lt;0.05 to\n                    <jats:italic>P<\/jats:italic>\n                    &lt;0.001) in all desHis\n                    <jats:sup>1<\/jats:sup>\n                    Pro\n                    <jats:sup>4<\/jats:sup>\n                    Glu\n                    <jats:sup>9<\/jats:sup>\n                    (Lys\n                    <jats:sup>12<\/jats:sup>\n                    PAL)-glucagon-treated mice. These studies highlight the potential of glucagon receptor inhibition alone, and in combination with GIP receptor activation, for T2DM treatment.\n                  <\/jats:p>","DOI":"10.1530\/joe-15-0463","type":"journal-article","created":{"date-parts":[[2016,4,21]],"date-time":"2016-04-21T00:47:47Z","timestamp":1461199667000},"page":"319-330","update-policy":"https:\/\/doi.org\/10.1530\/crossmarkpolicy-5","source":"Crossref","is-referenced-by-count":11,"title":["Glucagon receptor antagonist and GIP agonist combination for diet-induced obese mice"],"prefix":"10.1530","volume":"229","author":[{"given":"L M","family":"McShane","sequence":"first","affiliation":[{"name":"1SAAD Centre for Pharmacy and DiabetesUniversity of Ulster, Coleraine, Northern Ireland, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"N","family":"Irwin","sequence":"additional","affiliation":[{"name":"1SAAD Centre for Pharmacy and DiabetesUniversity of Ulster, Coleraine, Northern Ireland, 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