Comparison of the anti-diabetic effects of GIP- and GLP-1-receptor activation in obese diabetic (ob/ob) mice: studies with DPP IV resistant N-AcGIP and exendin(1-39)amide

Nigel Irwin, Paula McClean, Roslyn S Cassidy, Finbarr O'Harte, Brian D Green, Victor Gault, Patrick Harriott, Peter Flatt

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Abstract

Background The two major incretin hormones, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are being actively explored as anti-diabetic agents because they lower blood glucose through multiple mechanisms. The rapid inactivation of GIP and GLP-1 by the ubiquitous enzyme, dipeptidyl peptidase IV (DPP IV) makes their biological actions short-lived, but stable agonists such as N-acetylated GIP (N-AcGIP) and exendin(1-39)amide have been advocated as stable and specific GIP and GLP-1 analogues. Methods The present study examined the sub-chronic (14days) antidiabetic actions of single daily doses of N-AcGIP and exendin(1-39)amide given alone or in combination to obese diabetic (ob/ob) mice over a 14-day period. Results Initial experiments confirmed the potent anti-hyperglycaemic and insulinotropic properties of N-AcGIP and exendin(1-39)amide. Sub-chronic administration of N-AcGIP alone or in combination with exendin(1-39)amide significantly decreased non-fasting plasma glucose and improved glucose tolerance compared to control ob/ob mice. This was associated with a significant enhancement of the insulin response to glucose and a notable improvement of insulin sensitivity. Combined treatment with N-AcGIP and exendin(1-39)amide also significantly decreased glycated haemoglobin. Exendin(1-39)amide alone had no significant effect on any of the metabolic parameters monitored. in addition, no significant effects were observed on body weight and food intake in any of the treatment groups. Conclusions The results illustrate significant anti-diabetic potential of NAcGIP alone and in combination with exendin(1-39)amide. Copyright (c) 2007 John Wiley & Sons, Ltd.
LanguageEnglish
Pages572-579
JournalDIABETES-METABOLISM RESEARCH AND REVIEWS
Volume23
Issue number7
DOIs
Publication statusPublished - Oct 2007

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Dipeptidyl Peptidase 4
Amides
Glucose
Peptides
Glucagon-Like Peptide 1
Incretins
Glycosylated Hemoglobin A
Glucagon-Like Peptide-1 Receptor
gastric inhibitory polypeptide (1-39)
helospectin I
Nuclear Family
Hypoglycemic Agents
Insulin Resistance
Blood Glucose
Eating
Body Weight
Hormones
Insulin
Enzymes

Cite this

@article{2ec7d5c58de74aed940049f1f3c20cb7,
title = "Comparison of the anti-diabetic effects of GIP- and GLP-1-receptor activation in obese diabetic (ob/ob) mice: studies with DPP IV resistant N-AcGIP and exendin(1-39)amide",
abstract = "Background The two major incretin hormones, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are being actively explored as anti-diabetic agents because they lower blood glucose through multiple mechanisms. The rapid inactivation of GIP and GLP-1 by the ubiquitous enzyme, dipeptidyl peptidase IV (DPP IV) makes their biological actions short-lived, but stable agonists such as N-acetylated GIP (N-AcGIP) and exendin(1-39)amide have been advocated as stable and specific GIP and GLP-1 analogues. Methods The present study examined the sub-chronic (14days) antidiabetic actions of single daily doses of N-AcGIP and exendin(1-39)amide given alone or in combination to obese diabetic (ob/ob) mice over a 14-day period. Results Initial experiments confirmed the potent anti-hyperglycaemic and insulinotropic properties of N-AcGIP and exendin(1-39)amide. Sub-chronic administration of N-AcGIP alone or in combination with exendin(1-39)amide significantly decreased non-fasting plasma glucose and improved glucose tolerance compared to control ob/ob mice. This was associated with a significant enhancement of the insulin response to glucose and a notable improvement of insulin sensitivity. Combined treatment with N-AcGIP and exendin(1-39)amide also significantly decreased glycated haemoglobin. Exendin(1-39)amide alone had no significant effect on any of the metabolic parameters monitored. in addition, no significant effects were observed on body weight and food intake in any of the treatment groups. Conclusions The results illustrate significant anti-diabetic potential of NAcGIP alone and in combination with exendin(1-39)amide. Copyright (c) 2007 John Wiley & Sons, Ltd.",
author = "Nigel Irwin and Paula McClean and Cassidy, {Roslyn S} and Finbarr O'Harte and Green, {Brian D} and Victor Gault and Patrick Harriott and Peter Flatt",
year = "2007",
month = "10",
doi = "10.1002/dmrr.729",
language = "English",
volume = "23",
pages = "572--579",
journal = "Diabetes/Metabolism Research and Reviews",
issn = "1520-7552",
number = "7",

}

TY - JOUR

T1 - Comparison of the anti-diabetic effects of GIP- and GLP-1-receptor activation in obese diabetic (ob/ob) mice: studies with DPP IV resistant N-AcGIP and exendin(1-39)amide

AU - Irwin, Nigel

AU - McClean, Paula

AU - Cassidy, Roslyn S

AU - O'Harte, Finbarr

AU - Green, Brian D

AU - Gault, Victor

AU - Harriott, Patrick

AU - Flatt, Peter

PY - 2007/10

Y1 - 2007/10

N2 - Background The two major incretin hormones, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are being actively explored as anti-diabetic agents because they lower blood glucose through multiple mechanisms. The rapid inactivation of GIP and GLP-1 by the ubiquitous enzyme, dipeptidyl peptidase IV (DPP IV) makes their biological actions short-lived, but stable agonists such as N-acetylated GIP (N-AcGIP) and exendin(1-39)amide have been advocated as stable and specific GIP and GLP-1 analogues. Methods The present study examined the sub-chronic (14days) antidiabetic actions of single daily doses of N-AcGIP and exendin(1-39)amide given alone or in combination to obese diabetic (ob/ob) mice over a 14-day period. Results Initial experiments confirmed the potent anti-hyperglycaemic and insulinotropic properties of N-AcGIP and exendin(1-39)amide. Sub-chronic administration of N-AcGIP alone or in combination with exendin(1-39)amide significantly decreased non-fasting plasma glucose and improved glucose tolerance compared to control ob/ob mice. This was associated with a significant enhancement of the insulin response to glucose and a notable improvement of insulin sensitivity. Combined treatment with N-AcGIP and exendin(1-39)amide also significantly decreased glycated haemoglobin. Exendin(1-39)amide alone had no significant effect on any of the metabolic parameters monitored. in addition, no significant effects were observed on body weight and food intake in any of the treatment groups. Conclusions The results illustrate significant anti-diabetic potential of NAcGIP alone and in combination with exendin(1-39)amide. Copyright (c) 2007 John Wiley & Sons, Ltd.

AB - Background The two major incretin hormones, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are being actively explored as anti-diabetic agents because they lower blood glucose through multiple mechanisms. The rapid inactivation of GIP and GLP-1 by the ubiquitous enzyme, dipeptidyl peptidase IV (DPP IV) makes their biological actions short-lived, but stable agonists such as N-acetylated GIP (N-AcGIP) and exendin(1-39)amide have been advocated as stable and specific GIP and GLP-1 analogues. Methods The present study examined the sub-chronic (14days) antidiabetic actions of single daily doses of N-AcGIP and exendin(1-39)amide given alone or in combination to obese diabetic (ob/ob) mice over a 14-day period. Results Initial experiments confirmed the potent anti-hyperglycaemic and insulinotropic properties of N-AcGIP and exendin(1-39)amide. Sub-chronic administration of N-AcGIP alone or in combination with exendin(1-39)amide significantly decreased non-fasting plasma glucose and improved glucose tolerance compared to control ob/ob mice. This was associated with a significant enhancement of the insulin response to glucose and a notable improvement of insulin sensitivity. Combined treatment with N-AcGIP and exendin(1-39)amide also significantly decreased glycated haemoglobin. Exendin(1-39)amide alone had no significant effect on any of the metabolic parameters monitored. in addition, no significant effects were observed on body weight and food intake in any of the treatment groups. Conclusions The results illustrate significant anti-diabetic potential of NAcGIP alone and in combination with exendin(1-39)amide. Copyright (c) 2007 John Wiley & Sons, Ltd.

U2 - 10.1002/dmrr.729

DO - 10.1002/dmrr.729

M3 - Article

VL - 23

SP - 572

EP - 579

JO - Diabetes/Metabolism Research and Reviews

T2 - Diabetes/Metabolism Research and Reviews

JF - Diabetes/Metabolism Research and Reviews

SN - 1520-7552

IS - 7

ER -