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

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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.
LanguageEnglish
Pages690-701
JournalBritish Journal of Pharmacology
Volume155
Issue number5
DOIs
Publication statusPublished - Nov 2008

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Gastric Inhibitory Polypeptide
Obesity
Therapeutics
pro-glucose-dependent insulinotropic polypeptide
Insulin
Glucose
Fats
Body Weight
Diet
Dipeptidyl Peptidase 4
Injections

Cite this

@article{1e21fb2b7da84d76bf77f146386c5098,
title = "(Pro(3)) GIP[mPEG]: novel, long-acting, mPEGylated antagonist of gastric inhibitory polypeptide for obesity-diabetes (diabesity) therapy",
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.",
author = "Paula McClean and Nigel Irwin and Kerry Hunter and Victor Gault and Peter Flatt",
year = "2008",
month = "11",
doi = "10.1038/bjp.2008.317",
language = "English",
volume = "155",
pages = "690--701",
journal = "British Journal of Pharmacology",
issn = "0007-1188",
number = "5",

}

TY - JOUR

T1 - (Pro(3)) GIP[mPEG]: novel, long-acting, mPEGylated antagonist of gastric inhibitory polypeptide for obesity-diabetes (diabesity) therapy

AU - McClean, Paula

AU - Irwin, Nigel

AU - Hunter, Kerry

AU - Gault, Victor

AU - Flatt, Peter

PY - 2008/11

Y1 - 2008/11

N2 - 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.

AB - 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.

U2 - 10.1038/bjp.2008.317

DO - 10.1038/bjp.2008.317

M3 - Article

VL - 155

SP - 690

EP - 701

JO - British Journal of Pharmacology

T2 - British Journal of Pharmacology

JF - British Journal of Pharmacology

SN - 0007-1188

IS - 5

ER -