Early administration of the glucose-dependent insulinotropic polypeptide receptor antagonist (Pro(3))GIP prevents the development of diabetes and related metabolic abnormalities associated with genetically inherited obesity in ob/ob mice

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Abstract

Aims/hypothesis Ablation of gastric inhibitory polypeptide ( GIP) receptor action is reported to protect against obesity and associated metabolic abnormalities. The aim of this study was to use prediabetic ob/ob mice to examine whether 60 days of chemical GIP receptor ablation with (Pro(3)) GIP is able to counter the development of genetic obesity-related diabetes. Materials and methods Young ( 5 - 7 weeks) ob/ob mice received once daily i.p. injections of either saline vehicle or (Pro(3)) GIP (25 nmol kg(-1) day(-1)) over a 60 day period. Food intake, body weight and circulating glucose and insulin were measured at frequent intervals. At 60 days, glucose tolerance, response to native GIP, postprandial responses, insulin sensitivity, HbA(1c), circulating hormones and plasma lipids were assessed. Results Body weight and food intake in (Pro(3)) GIP-treated mice did not differ from ob/ob controls. GIP receptor blockade significantly improved non-fasting glucose ( p <0.001), HbA(1c) ( p <0.05), glucose tolerance (p <0.001), meal tolerance ( p <0.001) and insulin sensitivity ( p <0.05). Remarkably, (Pro(3)) GIP treatment prevented the age-related development of diabetes, as none of these parameters differed significantly between treated ob/ob mice and normal age-matched lean controls. Circulating levels of glucagon, corticosterone, adiponectin and total cholesterol were unchanged by (Pro(3)) GIP, while levels of triacylglycerol, LDL-cholesterol and resistin were decreased ( p <0.05) compared with those in control ob/ob mice. Plasma and pancreatic insulin concentrations were generally lower after (Pro(3)) GIP treatment than in control ob/ob mice ( p <0.01), but plasma insulin levels remained substantially raised ( p <0.001) compared with those observed in lean controls. Conclusions/interpretation These data indicate that sustained GIP receptor antagonism provides an effective means of preventing the development of many of the metabolic abnormalities of obesity-driven diabetes.
LanguageEnglish
Pages1532-1540
JournalDiabetologia
Volume50
Issue number7
DOIs
Publication statusPublished - Jul 2007

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Obesity
Glucose
Insulin
Insulin Resistance
Eating
Body Weight
Gastric Inhibitory Polypeptide
Resistin
Adiponectin
Corticosterone
Glucagon
LDL Cholesterol
Meals
pro-glucose-dependent insulinotropic polypeptide
gastric inhibitory polypeptide receptor
Cholesterol
Hormones
Lipids
Injections
Therapeutics

Cite this

@article{280ad2626f9a46d4ab99b1d3502bd64f,
title = "Early administration of the glucose-dependent insulinotropic polypeptide receptor antagonist (Pro(3))GIP prevents the development of diabetes and related metabolic abnormalities associated with genetically inherited obesity in ob/ob mice",
abstract = "Aims/hypothesis Ablation of gastric inhibitory polypeptide ( GIP) receptor action is reported to protect against obesity and associated metabolic abnormalities. The aim of this study was to use prediabetic ob/ob mice to examine whether 60 days of chemical GIP receptor ablation with (Pro(3)) GIP is able to counter the development of genetic obesity-related diabetes. Materials and methods Young ( 5 - 7 weeks) ob/ob mice received once daily i.p. injections of either saline vehicle or (Pro(3)) GIP (25 nmol kg(-1) day(-1)) over a 60 day period. Food intake, body weight and circulating glucose and insulin were measured at frequent intervals. At 60 days, glucose tolerance, response to native GIP, postprandial responses, insulin sensitivity, HbA(1c), circulating hormones and plasma lipids were assessed. Results Body weight and food intake in (Pro(3)) GIP-treated mice did not differ from ob/ob controls. GIP receptor blockade significantly improved non-fasting glucose ( p <0.001), HbA(1c) ( p <0.05), glucose tolerance (p <0.001), meal tolerance ( p <0.001) and insulin sensitivity ( p <0.05). Remarkably, (Pro(3)) GIP treatment prevented the age-related development of diabetes, as none of these parameters differed significantly between treated ob/ob mice and normal age-matched lean controls. Circulating levels of glucagon, corticosterone, adiponectin and total cholesterol were unchanged by (Pro(3)) GIP, while levels of triacylglycerol, LDL-cholesterol and resistin were decreased ( p <0.05) compared with those in control ob/ob mice. Plasma and pancreatic insulin concentrations were generally lower after (Pro(3)) GIP treatment than in control ob/ob mice ( p <0.01), but plasma insulin levels remained substantially raised ( p <0.001) compared with those observed in lean controls. Conclusions/interpretation These data indicate that sustained GIP receptor antagonism provides an effective means of preventing the development of many of the metabolic abnormalities of obesity-driven diabetes.",
author = "Nigel Irwin and Paula McClean and Finbarr O'Harte and Victor Gault and P Harriott and Peter Flatt",
year = "2007",
month = "7",
doi = "10.1007/s00125-007-0692-2",
language = "English",
volume = "50",
pages = "1532--1540",
journal = "Diabetologia",
issn = "0012-186X",
number = "7",

}

TY - JOUR

T1 - Early administration of the glucose-dependent insulinotropic polypeptide receptor antagonist (Pro(3))GIP prevents the development of diabetes and related metabolic abnormalities associated with genetically inherited obesity in ob/ob mice

AU - Irwin, Nigel

AU - McClean, Paula

AU - O'Harte, Finbarr

AU - Gault, Victor

AU - Harriott, P

AU - Flatt, Peter

PY - 2007/7

Y1 - 2007/7

N2 - Aims/hypothesis Ablation of gastric inhibitory polypeptide ( GIP) receptor action is reported to protect against obesity and associated metabolic abnormalities. The aim of this study was to use prediabetic ob/ob mice to examine whether 60 days of chemical GIP receptor ablation with (Pro(3)) GIP is able to counter the development of genetic obesity-related diabetes. Materials and methods Young ( 5 - 7 weeks) ob/ob mice received once daily i.p. injections of either saline vehicle or (Pro(3)) GIP (25 nmol kg(-1) day(-1)) over a 60 day period. Food intake, body weight and circulating glucose and insulin were measured at frequent intervals. At 60 days, glucose tolerance, response to native GIP, postprandial responses, insulin sensitivity, HbA(1c), circulating hormones and plasma lipids were assessed. Results Body weight and food intake in (Pro(3)) GIP-treated mice did not differ from ob/ob controls. GIP receptor blockade significantly improved non-fasting glucose ( p <0.001), HbA(1c) ( p <0.05), glucose tolerance (p <0.001), meal tolerance ( p <0.001) and insulin sensitivity ( p <0.05). Remarkably, (Pro(3)) GIP treatment prevented the age-related development of diabetes, as none of these parameters differed significantly between treated ob/ob mice and normal age-matched lean controls. Circulating levels of glucagon, corticosterone, adiponectin and total cholesterol were unchanged by (Pro(3)) GIP, while levels of triacylglycerol, LDL-cholesterol and resistin were decreased ( p <0.05) compared with those in control ob/ob mice. Plasma and pancreatic insulin concentrations were generally lower after (Pro(3)) GIP treatment than in control ob/ob mice ( p <0.01), but plasma insulin levels remained substantially raised ( p <0.001) compared with those observed in lean controls. Conclusions/interpretation These data indicate that sustained GIP receptor antagonism provides an effective means of preventing the development of many of the metabolic abnormalities of obesity-driven diabetes.

AB - Aims/hypothesis Ablation of gastric inhibitory polypeptide ( GIP) receptor action is reported to protect against obesity and associated metabolic abnormalities. The aim of this study was to use prediabetic ob/ob mice to examine whether 60 days of chemical GIP receptor ablation with (Pro(3)) GIP is able to counter the development of genetic obesity-related diabetes. Materials and methods Young ( 5 - 7 weeks) ob/ob mice received once daily i.p. injections of either saline vehicle or (Pro(3)) GIP (25 nmol kg(-1) day(-1)) over a 60 day period. Food intake, body weight and circulating glucose and insulin were measured at frequent intervals. At 60 days, glucose tolerance, response to native GIP, postprandial responses, insulin sensitivity, HbA(1c), circulating hormones and plasma lipids were assessed. Results Body weight and food intake in (Pro(3)) GIP-treated mice did not differ from ob/ob controls. GIP receptor blockade significantly improved non-fasting glucose ( p <0.001), HbA(1c) ( p <0.05), glucose tolerance (p <0.001), meal tolerance ( p <0.001) and insulin sensitivity ( p <0.05). Remarkably, (Pro(3)) GIP treatment prevented the age-related development of diabetes, as none of these parameters differed significantly between treated ob/ob mice and normal age-matched lean controls. Circulating levels of glucagon, corticosterone, adiponectin and total cholesterol were unchanged by (Pro(3)) GIP, while levels of triacylglycerol, LDL-cholesterol and resistin were decreased ( p <0.05) compared with those in control ob/ob mice. Plasma and pancreatic insulin concentrations were generally lower after (Pro(3)) GIP treatment than in control ob/ob mice ( p <0.01), but plasma insulin levels remained substantially raised ( p <0.001) compared with those observed in lean controls. Conclusions/interpretation These data indicate that sustained GIP receptor antagonism provides an effective means of preventing the development of many of the metabolic abnormalities of obesity-driven diabetes.

U2 - 10.1007/s00125-007-0692-2

DO - 10.1007/s00125-007-0692-2

M3 - Article

VL - 50

SP - 1532

EP - 1540

JO - Diabetologia

T2 - Diabetologia

JF - Diabetologia

SN - 0012-186X

IS - 7

ER -