Comparison of independent and combined metabolic effects of chronic treatment with (pGlu-Gln)-CCK-8 and long-acting GLP-1 and GIP mimetics in high fat fed mice.

Nigel Irwin, K Hunter, IA Montgomery, Peter Flatt

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Abstract

AIM: The incretin hormones, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), and cholecystokinin (CCK) are gastrointestinal peptides with important physiological effects. However, rapid enzymatic degradation results in short-lived biological actions.METHODS: The present study has examined metabolic actions of exendin-4, GIP[mPEG] and a novel CCK-8 analogue, (pGlu-Gln)-CCK-8 as enzymatically, stable forms of GLP-1, GIP and CCK, respectively.RESULTS: All peptides significantly (p <0.01 to p <0.001) stimulated insulin secretion from BRIN BD11 cells, and acute in vivo experiments confirmed prominent antihyperglycaemic and insulinotropic responses to GLP-1 or GIP receptor activation in normal mice. Twice daily injection of (pGlu-Gln)-CCK-8 alone and in combination with exendin-4 or GIP[mPEG] in high fat fed mice significantly decreased accumulated food intake (p <0.05 to p <0.01), body weight gain (p <0.05 to p <0.01) and improved (p <0.05) insulin sensitivity in high fat fed mice. However, there was no evidence for superior effects compared to (pGlu-Gln)-CCK-8 alone. Combined treatment of (pGlu-Gln)-CCK-8 and exendin-4 resulted in significantly (p <0.05) lowered circulating glucose levels and improved (p <0.05) intraperitoneal glucose tolerance. These effects were superior to either treatment regime alone but not associated with altered insulin concentrations. A single injection of (pGlu-Gln)-CCK-8, or combined with exendin-4, significantly (p <0.05) lowered blood glucose levels 24 hours post injection in untreated high fat fed mice.CONCLUSION: These studies highlight the potential of (pGlu-Gln)-CCK-8 alone and in combination with incretin hormones for the treatment of type 2 diabetes.
LanguageEnglish
Pages650-659
JournalDiabetes Obesity and Matabolism
Volume15
Issue number7
DOIs
Publication statusPublished - 6 Jan 2013

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Glucagon-Like Peptide 1
Fats
Glucose
Peptides
Incretins
Cholecystokinin
Therapeutics
Injections
Hormones
Insulin
cholecystokinin 8
Hypoglycemic Agents
Type 2 Diabetes Mellitus
Weight Gain
Insulin Resistance
Blood Glucose
Eating
Body Weight
exenatide

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@article{1370b8d5e5794e57a0d1801ef874ed1d,
title = "Comparison of independent and combined metabolic effects of chronic treatment with (pGlu-Gln)-CCK-8 and long-acting GLP-1 and GIP mimetics in high fat fed mice.",
abstract = "AIM: The incretin hormones, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), and cholecystokinin (CCK) are gastrointestinal peptides with important physiological effects. However, rapid enzymatic degradation results in short-lived biological actions.METHODS: The present study has examined metabolic actions of exendin-4, GIP[mPEG] and a novel CCK-8 analogue, (pGlu-Gln)-CCK-8 as enzymatically, stable forms of GLP-1, GIP and CCK, respectively.RESULTS: All peptides significantly (p <0.01 to p <0.001) stimulated insulin secretion from BRIN BD11 cells, and acute in vivo experiments confirmed prominent antihyperglycaemic and insulinotropic responses to GLP-1 or GIP receptor activation in normal mice. Twice daily injection of (pGlu-Gln)-CCK-8 alone and in combination with exendin-4 or GIP[mPEG] in high fat fed mice significantly decreased accumulated food intake (p <0.05 to p <0.01), body weight gain (p <0.05 to p <0.01) and improved (p <0.05) insulin sensitivity in high fat fed mice. However, there was no evidence for superior effects compared to (pGlu-Gln)-CCK-8 alone. Combined treatment of (pGlu-Gln)-CCK-8 and exendin-4 resulted in significantly (p <0.05) lowered circulating glucose levels and improved (p <0.05) intraperitoneal glucose tolerance. These effects were superior to either treatment regime alone but not associated with altered insulin concentrations. A single injection of (pGlu-Gln)-CCK-8, or combined with exendin-4, significantly (p <0.05) lowered blood glucose levels 24 hours post injection in untreated high fat fed mice.CONCLUSION: These studies highlight the potential of (pGlu-Gln)-CCK-8 alone and in combination with incretin hormones for the treatment of type 2 diabetes.",
author = "Nigel Irwin and K Hunter and IA Montgomery and Peter Flatt",
year = "2013",
month = "1",
day = "6",
doi = "10.1111/dom.12079",
language = "English",
volume = "15",
pages = "650--659",
journal = "Diabetes, Obesity and Metabolism",
issn = "1463-1326",
number = "7",

}

TY - JOUR

T1 - Comparison of independent and combined metabolic effects of chronic treatment with (pGlu-Gln)-CCK-8 and long-acting GLP-1 and GIP mimetics in high fat fed mice.

AU - Irwin, Nigel

AU - Hunter, K

AU - Montgomery, IA

AU - Flatt, Peter

PY - 2013/1/6

Y1 - 2013/1/6

N2 - AIM: The incretin hormones, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), and cholecystokinin (CCK) are gastrointestinal peptides with important physiological effects. However, rapid enzymatic degradation results in short-lived biological actions.METHODS: The present study has examined metabolic actions of exendin-4, GIP[mPEG] and a novel CCK-8 analogue, (pGlu-Gln)-CCK-8 as enzymatically, stable forms of GLP-1, GIP and CCK, respectively.RESULTS: All peptides significantly (p <0.01 to p <0.001) stimulated insulin secretion from BRIN BD11 cells, and acute in vivo experiments confirmed prominent antihyperglycaemic and insulinotropic responses to GLP-1 or GIP receptor activation in normal mice. Twice daily injection of (pGlu-Gln)-CCK-8 alone and in combination with exendin-4 or GIP[mPEG] in high fat fed mice significantly decreased accumulated food intake (p <0.05 to p <0.01), body weight gain (p <0.05 to p <0.01) and improved (p <0.05) insulin sensitivity in high fat fed mice. However, there was no evidence for superior effects compared to (pGlu-Gln)-CCK-8 alone. Combined treatment of (pGlu-Gln)-CCK-8 and exendin-4 resulted in significantly (p <0.05) lowered circulating glucose levels and improved (p <0.05) intraperitoneal glucose tolerance. These effects were superior to either treatment regime alone but not associated with altered insulin concentrations. A single injection of (pGlu-Gln)-CCK-8, or combined with exendin-4, significantly (p <0.05) lowered blood glucose levels 24 hours post injection in untreated high fat fed mice.CONCLUSION: These studies highlight the potential of (pGlu-Gln)-CCK-8 alone and in combination with incretin hormones for the treatment of type 2 diabetes.

AB - AIM: The incretin hormones, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), and cholecystokinin (CCK) are gastrointestinal peptides with important physiological effects. However, rapid enzymatic degradation results in short-lived biological actions.METHODS: The present study has examined metabolic actions of exendin-4, GIP[mPEG] and a novel CCK-8 analogue, (pGlu-Gln)-CCK-8 as enzymatically, stable forms of GLP-1, GIP and CCK, respectively.RESULTS: All peptides significantly (p <0.01 to p <0.001) stimulated insulin secretion from BRIN BD11 cells, and acute in vivo experiments confirmed prominent antihyperglycaemic and insulinotropic responses to GLP-1 or GIP receptor activation in normal mice. Twice daily injection of (pGlu-Gln)-CCK-8 alone and in combination with exendin-4 or GIP[mPEG] in high fat fed mice significantly decreased accumulated food intake (p <0.05 to p <0.01), body weight gain (p <0.05 to p <0.01) and improved (p <0.05) insulin sensitivity in high fat fed mice. However, there was no evidence for superior effects compared to (pGlu-Gln)-CCK-8 alone. Combined treatment of (pGlu-Gln)-CCK-8 and exendin-4 resulted in significantly (p <0.05) lowered circulating glucose levels and improved (p <0.05) intraperitoneal glucose tolerance. These effects were superior to either treatment regime alone but not associated with altered insulin concentrations. A single injection of (pGlu-Gln)-CCK-8, or combined with exendin-4, significantly (p <0.05) lowered blood glucose levels 24 hours post injection in untreated high fat fed mice.CONCLUSION: These studies highlight the potential of (pGlu-Gln)-CCK-8 alone and in combination with incretin hormones for the treatment of type 2 diabetes.

U2 - 10.1111/dom.12079

DO - 10.1111/dom.12079

M3 - Article

VL - 15

SP - 650

EP - 659

JO - Diabetes, Obesity and Metabolism

T2 - Diabetes, Obesity and Metabolism

JF - Diabetes, Obesity and Metabolism

SN - 1463-1326

IS - 7

ER -