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(Pro(3)) GIP[mPEG]: novel, long-acting, mPEGylated antagonist of gastric inhibitory polypeptide for obesity-diabetes (diabesity) therapy

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McClean, Paula, Irwin, Nigel, Hunter, Kerry, Gault, Victor and Flatt, Peter (2008) (Pro(3)) GIP[mPEG]: novel, long-acting, mPEGylated antagonist of gastric inhibitory polypeptide for obesity-diabetes (diabesity) therapy. BRITISH JOURNAL OF PHARMACOLOGY, 155 (5). pp. 690-701. [Journal article]

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DOI: 10.1038/bjp.2008.317

Abstract

Background and purpose: Antagonism of the gastric inhibitory polypeptide (GIP) receptor with daily injection of proline-3 gastric inhibitory polypeptide ((Pro 3) GIP) can reverse or prevent many of the metabolic abnormalities associated with diet-induced obesity-diabetes (diabesity). This study has examined the ability of a novel and longer-acting form of (Pro 3) GIP, (Pro 3) GIP mini-polyethylene glycol ((Pro 3) GIP[ mPEG]), to counter diet-induced diabesity in mice, using a daily and intermittent dosing regime. Experimental approach: We studied the actions of (Pro 3) GIP[ mPEG] at the GIP receptor in vitro and in vivo in both dietary and genetic diabesity. Key results: (Pro 3) GIP[ mPEG] was completely resistant to degradation by dipeptidyl peptidase IV. (Pro 3) GIP[mPEG] inhibited GIP-induced cAMP and insulin production in vitro. A greater and prolonged antagonism of GIP-induced glucose-lowering action was followed (Pro 3) GIP[mPEG] administration, compared with (Pro 3) GIP. In contrast with (Pro 3) GIP, mice injected once every 3 days for 48 days with (Pro 3) GIP[mPEG] displayed reduced body weight gain and hyperinsulinemia with improved glucose tolerance and insulin secretory responses, compared with high-fat-fed controls. Daily i.p. injection of (Pro 3) GIP, (Pro 3) GIP[mPEG] or (Pro 3) GIP b.i.d. for 21 days also decreased body weight, circulating plasma insulin levels and improved glucose tolerance, compared with high-fat controls. Plasma triglycerides were decreased by (Pro 3) GIP[mPEG] and (Pro 3) GIP b.i.d. treatment groups. The observed changes were accompanied by enhancement of insulin sensitivity in all treatment regimes. (Pro 3) GIP[mPEG] was also effective over 16 days treatment of genetically obese-diabetic ob/ob mice. Conclusions and implications: These data demonstrate the utility of GIP receptor antagonism for the treatment of diabesity and the potential offered by (Pro 3) GIP[mPEG] as a long-acting stable GIP receptor antagonist.

Item Type:Journal article
Faculties and Schools:Faculty of Life and Health Sciences
Faculty of Life and Health Sciences > School of Biomedical Sciences
Faculty of Life and Health Sciences > School of Pharmacy and Pharmaceutical Science
Research Institutes and Groups:Biomedical Sciences Research Institute
Biomedical Sciences Research Institute > Diabetes
Biomedical Sciences Research Institute > Stratified Medicine
ID Code:2910
Deposited By:Professor Peter Flatt
Deposited On:17 Dec 2009 09:42
Last Modified:15 Oct 2013 16:38

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