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- Title
(Pro(3))GIP[mPEG]: novel, long-acting, mPEGylated antagonist of gastric inhibitory polypeptide for obesity-diabetes (diabesity) therapy.
- Authors
McClean, P. L.; Irwin, N.; Hunter, K.; Gault, V. A.; Flatt, P. R.
- Abstract
Background and purpose:Antagonism of the gastric inhibitory polypeptide (GIP) receptor with daily injection of proline-3 gastric inhibitory polypeptide ((Pro3)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 (Pro3)GIP, (Pro3)GIP mini-polyethylene glycol ((Pro3)GIP[mPEG]), to counter diet-induced diabesity in mice, using a daily and intermittent dosing regime.Experimental approach:We studied the actions of (Pro3)GIP[mPEG] at the GIP receptor in vitro and in vivo in both dietary and genetic diabesity.Key results:(Pro3)GIP[mPEG] was completely resistant to degradation by dipeptidyl peptidase IV. (Pro3)GIP[mPEG] inhibited GIP-induced cAMP and insulin production in vitro. A greater and prolonged antagonism of GIP-induced glucose-lowering action was followed (Pro3)GIP[mPEG] administration, compared with (Pro3)GIP. In contrast with (Pro3)GIP, mice injected once every 3 days for 48 days with (Pro3)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 (Pro3)GIP, (Pro3)GIP[mPEG] or (Pro3)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 (Pro3)GIP[mPEG] and (Pro3)GIP b.i.d. treatment groups. The observed changes were accompanied by enhancement of insulin sensitivity in all treatment regimes. (Pro3)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 (Pro3)GIP[mPEG] as a long-acting stable GIP receptor antagonist.British Journal of Pharmacology (2008) 155, 690–701; doi:10.1038/bjp.2008.317; published online 11 August 2008
- Subjects
OBESITY; POLYPEPTIDES; DIABETES; ENZYME inhibitors; INSULIN antagonists; LABORATORY mice; OVERWEIGHT persons; PROLINE
- Publication
British Journal of Pharmacology, 2008, Vol 155, Issue 5, p690
- ISSN
0007-1188
- Publication type
journal article
- DOI
10.1038/bjp.2008.317