{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T08:29:21Z","timestamp":1785227361391,"version":"3.55.0"},"reference-count":31,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2009,1,29]],"date-time":"2009-01-29T00:00:00Z","timestamp":1233187200000},"content-version":"vor","delay-in-days":89,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["bpspubs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["British J Pharmacology"],"published-print":{"date-parts":[[2008,11]]},"abstract":"<jats:sec><jats:title>Background and purpose:<\/jats:title><jats:p>Antagonism of the gastric inhibitory polypeptide (GIP) receptor with daily injection of proline\u20103 gastric inhibitory polypeptide ((Pro<jats:sup>3<\/jats:sup>)GIP) can reverse or prevent many of the metabolic abnormalities associated with diet\u2010induced obesity\u2010diabetes (diabesity). This study has examined the ability of a novel and longer\u2010acting form of (Pro<jats:sup>3<\/jats:sup>)GIP, (Pro<jats:sup>3<\/jats:sup>)GIP mini\u2010polyethylene glycol ((Pro<jats:sup>3<\/jats:sup>)GIP[mPEG]), to counter diet\u2010induced diabesity in mice, using a daily and intermittent dosing regime.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental approach:<\/jats:title><jats:p>We studied the actions of (Pro<jats:sup>3<\/jats:sup>)GIP[mPEG] at the GIP receptor <jats:italic>in vitro<\/jats:italic> and <jats:italic>in vivo<\/jats:italic> in both dietary and genetic diabesity.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key results:<\/jats:title><jats:p>(Pro<jats:sup>3<\/jats:sup>)GIP[mPEG] was completely resistant to degradation by dipeptidyl peptidase IV. (Pro<jats:sup>3<\/jats:sup>)GIP[mPEG] inhibited GIP\u2010induced cAMP and insulin production <jats:italic>in vitro<\/jats:italic>. A greater and prolonged antagonism of GIP\u2010induced glucose\u2010lowering action was followed (Pro<jats:sup>3<\/jats:sup>)GIP[mPEG] administration, compared with (Pro<jats:sup>3<\/jats:sup>)GIP. In contrast with (Pro<jats:sup>3<\/jats:sup>)GIP, mice injected once every 3 days for 48 days with (Pro<jats:sup>3<\/jats:sup>)GIP[mPEG] displayed reduced body weight gain and hyperinsulinemia with improved glucose tolerance and insulin secretory responses, compared with high\u2010fat\u2010fed controls. Daily i.p. injection of (Pro<jats:sup>3<\/jats:sup>)GIP, (Pro<jats:sup>3<\/jats:sup>)GIP[mPEG] or (Pro<jats:sup>3<\/jats:sup>)GIP b.i.d. for 21 days also decreased body weight, circulating plasma insulin levels and improved glucose tolerance, compared with high\u2010fat controls. Plasma triglycerides were decreased by (Pro<jats:sup>3<\/jats:sup>)GIP[mPEG] and (Pro<jats:sup>3<\/jats:sup>)GIP b.i.d. treatment groups. The observed changes were accompanied by enhancement of insulin sensitivity in all treatment regimes. (Pro<jats:sup>3<\/jats:sup>)GIP[mPEG] was also effective over 16 days treatment of genetically obese\u2010diabetic <jats:italic>ob\/ob<\/jats:italic> mice.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions and implications:<\/jats:title><jats:p>These data demonstrate the utility of GIP receptor antagonism for the treatment of diabesity and the potential offered by (Pro<jats:sup>3<\/jats:sup>)GIP[mPEG] as a long\u2010acting stable GIP receptor antagonist.<\/jats:p><jats:p><jats:italic>British Journal of Pharmacology<\/jats:italic> (2008) <jats:bold>155<\/jats:bold>, 690\u2013701; doi:<jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"doi\" xlink:href=\"10.1038\/bjp.2008.317\">10.1038\/bjp.2008.317<\/jats:ext-link>; published online 11 August 2008<\/jats:p><\/jats:sec>","DOI":"10.1038\/bjp.2008.317","type":"journal-article","created":{"date-parts":[[2008,8,11]],"date-time":"2008-08-11T14:12:26Z","timestamp":1218463946000},"page":"690-701","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":41,"title":["(Pro<sup>3<\/sup>)GIP[mPEG]: novel, long\u2010acting, mPEGylated antagonist of gastric inhibitory polypeptide for obesity\u2010diabetes (diabesity) therapy"],"prefix":"10.1111","volume":"155","author":[{"given":"P L","family":"McClean","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"N","family":"Irwin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"K","family":"Hunter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"V 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