Beneficial effects of the novel cholecystokinin agonist (pGlu-Gln)-CCK-8 in mouse models of obesity/diabetes

Nigel Irwin, P Frizelle, IA Montgomery, RC Moffett, Finbarr O'Harte, Peter Flatt

Research output: Contribution to journalArticle

36 Citations (Scopus)

Abstract

AIMS/HYPOTHESIS: Cholecystokinin (CCK) is a rapidly degraded gastrointestinal peptide that stimulates satiety and insulin secretion. We aimed to investigate the beneficial weight-lowering and metabolic effects of the novel N-terminally modified CCK analogue, (pGlu-Gln)-CCK-8.METHODS: The biological actions of (pGlu-Gln)-CCK-8 were comprehensively evaluated in pancreatic clonal BRIN BD11 cells and in vivo in high-fat-fed and ob/ob mice.RESULTS: (pGlu-Gln)-CCK-8 was completely resistant to enzymatic degradation and its satiating effects were significantly (p <0.05 to p <0.001) more potent than CCK-8. In BRIN-BD11 cells, (pGlu-Gln)-CCK-8 exhibited enhanced (p <0.01 to p <0.001) insulinotropic actions compared with CCK-8. When administered acutely to high-fat-fed or ob/ob mice, (pGlu-Gln)-CCK-8 improved glucose homeostasis. Sub-chronic twice daily injections of (pGlu-Gln)-CCK-8 in high-fat-fed mice for 28 days significantly decreased body weight (p <0.05 to p <0.001), accumulated food intake (p <0.05 to p <0.001), non-fasting glucose (p <0.05) and triacylglycerol deposition in pancreatic (p <0.01), adipose (p <0.05) and liver (p <0.001) tissue, and improved oral (p <0.05) and i.p. (p <0.05) glucose tolerance and insulin sensitivity (p <0.001). Similar observations were noted in ob/ob mice given twice daily injections of (pGlu-Gln)-CCK-8. In addition, these beneficial effects were not reproduced by simple dietary restriction and were not associated with changes in energy expenditure. There was no evidence for development of tolerance to (pGlu-Gln)-CCK-8, and analysis of histology or blood-borne markers for pancreatic, liver and renal function in mice treated with (pGlu-Gln)-CCK-8 suggested little abnormal pathology.CONCLUSIONS/INTERPRETATION: These studies emphasise the potential of (pGlu-Gln)-CCK-8 for the alleviation of obesity and insulin resistance.
LanguageEnglish
Pages2747-2758
JournalDiabetologia
Volume55
Issue number10
Publication statusPublished - 20 Jul 2012

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Cholecystokinin
Obesity
Fats
Glucose
Insulin Resistance
cholecystokinin 8
Injections
Liver
Energy Metabolism
Histology
Triglycerides
Homeostasis
Eating
Body Weight
Insulin
Pathology

Cite this

@article{1f1095e262674573957d0fe322de2516,
title = "Beneficial effects of the novel cholecystokinin agonist (pGlu-Gln)-CCK-8 in mouse models of obesity/diabetes",
abstract = "AIMS/HYPOTHESIS: Cholecystokinin (CCK) is a rapidly degraded gastrointestinal peptide that stimulates satiety and insulin secretion. We aimed to investigate the beneficial weight-lowering and metabolic effects of the novel N-terminally modified CCK analogue, (pGlu-Gln)-CCK-8.METHODS: The biological actions of (pGlu-Gln)-CCK-8 were comprehensively evaluated in pancreatic clonal BRIN BD11 cells and in vivo in high-fat-fed and ob/ob mice.RESULTS: (pGlu-Gln)-CCK-8 was completely resistant to enzymatic degradation and its satiating effects were significantly (p <0.05 to p <0.001) more potent than CCK-8. In BRIN-BD11 cells, (pGlu-Gln)-CCK-8 exhibited enhanced (p <0.01 to p <0.001) insulinotropic actions compared with CCK-8. When administered acutely to high-fat-fed or ob/ob mice, (pGlu-Gln)-CCK-8 improved glucose homeostasis. Sub-chronic twice daily injections of (pGlu-Gln)-CCK-8 in high-fat-fed mice for 28 days significantly decreased body weight (p <0.05 to p <0.001), accumulated food intake (p <0.05 to p <0.001), non-fasting glucose (p <0.05) and triacylglycerol deposition in pancreatic (p <0.01), adipose (p <0.05) and liver (p <0.001) tissue, and improved oral (p <0.05) and i.p. (p <0.05) glucose tolerance and insulin sensitivity (p <0.001). Similar observations were noted in ob/ob mice given twice daily injections of (pGlu-Gln)-CCK-8. In addition, these beneficial effects were not reproduced by simple dietary restriction and were not associated with changes in energy expenditure. There was no evidence for development of tolerance to (pGlu-Gln)-CCK-8, and analysis of histology or blood-borne markers for pancreatic, liver and renal function in mice treated with (pGlu-Gln)-CCK-8 suggested little abnormal pathology.CONCLUSIONS/INTERPRETATION: These studies emphasise the potential of (pGlu-Gln)-CCK-8 for the alleviation of obesity and insulin resistance.",
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Beneficial effects of the novel cholecystokinin agonist (pGlu-Gln)-CCK-8 in mouse models of obesity/diabetes. / Irwin, Nigel; Frizelle, P; Montgomery, IA; Moffett, RC; O'Harte, Finbarr; Flatt, Peter.

In: Diabetologia, Vol. 55, No. 10, 20.07.2012, p. 2747-2758.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Beneficial effects of the novel cholecystokinin agonist (pGlu-Gln)-CCK-8 in mouse models of obesity/diabetes

AU - Irwin, Nigel

AU - Frizelle, P

AU - Montgomery, IA

AU - Moffett, RC

AU - O'Harte, Finbarr

AU - Flatt, Peter

PY - 2012/7/20

Y1 - 2012/7/20

N2 - AIMS/HYPOTHESIS: Cholecystokinin (CCK) is a rapidly degraded gastrointestinal peptide that stimulates satiety and insulin secretion. We aimed to investigate the beneficial weight-lowering and metabolic effects of the novel N-terminally modified CCK analogue, (pGlu-Gln)-CCK-8.METHODS: The biological actions of (pGlu-Gln)-CCK-8 were comprehensively evaluated in pancreatic clonal BRIN BD11 cells and in vivo in high-fat-fed and ob/ob mice.RESULTS: (pGlu-Gln)-CCK-8 was completely resistant to enzymatic degradation and its satiating effects were significantly (p <0.05 to p <0.001) more potent than CCK-8. In BRIN-BD11 cells, (pGlu-Gln)-CCK-8 exhibited enhanced (p <0.01 to p <0.001) insulinotropic actions compared with CCK-8. When administered acutely to high-fat-fed or ob/ob mice, (pGlu-Gln)-CCK-8 improved glucose homeostasis. Sub-chronic twice daily injections of (pGlu-Gln)-CCK-8 in high-fat-fed mice for 28 days significantly decreased body weight (p <0.05 to p <0.001), accumulated food intake (p <0.05 to p <0.001), non-fasting glucose (p <0.05) and triacylglycerol deposition in pancreatic (p <0.01), adipose (p <0.05) and liver (p <0.001) tissue, and improved oral (p <0.05) and i.p. (p <0.05) glucose tolerance and insulin sensitivity (p <0.001). Similar observations were noted in ob/ob mice given twice daily injections of (pGlu-Gln)-CCK-8. In addition, these beneficial effects were not reproduced by simple dietary restriction and were not associated with changes in energy expenditure. There was no evidence for development of tolerance to (pGlu-Gln)-CCK-8, and analysis of histology or blood-borne markers for pancreatic, liver and renal function in mice treated with (pGlu-Gln)-CCK-8 suggested little abnormal pathology.CONCLUSIONS/INTERPRETATION: These studies emphasise the potential of (pGlu-Gln)-CCK-8 for the alleviation of obesity and insulin resistance.

AB - AIMS/HYPOTHESIS: Cholecystokinin (CCK) is a rapidly degraded gastrointestinal peptide that stimulates satiety and insulin secretion. We aimed to investigate the beneficial weight-lowering and metabolic effects of the novel N-terminally modified CCK analogue, (pGlu-Gln)-CCK-8.METHODS: The biological actions of (pGlu-Gln)-CCK-8 were comprehensively evaluated in pancreatic clonal BRIN BD11 cells and in vivo in high-fat-fed and ob/ob mice.RESULTS: (pGlu-Gln)-CCK-8 was completely resistant to enzymatic degradation and its satiating effects were significantly (p <0.05 to p <0.001) more potent than CCK-8. In BRIN-BD11 cells, (pGlu-Gln)-CCK-8 exhibited enhanced (p <0.01 to p <0.001) insulinotropic actions compared with CCK-8. When administered acutely to high-fat-fed or ob/ob mice, (pGlu-Gln)-CCK-8 improved glucose homeostasis. Sub-chronic twice daily injections of (pGlu-Gln)-CCK-8 in high-fat-fed mice for 28 days significantly decreased body weight (p <0.05 to p <0.001), accumulated food intake (p <0.05 to p <0.001), non-fasting glucose (p <0.05) and triacylglycerol deposition in pancreatic (p <0.01), adipose (p <0.05) and liver (p <0.001) tissue, and improved oral (p <0.05) and i.p. (p <0.05) glucose tolerance and insulin sensitivity (p <0.001). Similar observations were noted in ob/ob mice given twice daily injections of (pGlu-Gln)-CCK-8. In addition, these beneficial effects were not reproduced by simple dietary restriction and were not associated with changes in energy expenditure. There was no evidence for development of tolerance to (pGlu-Gln)-CCK-8, and analysis of histology or blood-borne markers for pancreatic, liver and renal function in mice treated with (pGlu-Gln)-CCK-8 suggested little abnormal pathology.CONCLUSIONS/INTERPRETATION: These studies emphasise the potential of (pGlu-Gln)-CCK-8 for the alleviation of obesity and insulin resistance.

M3 - Article

VL - 55

SP - 2747

EP - 2758

JO - Diabetologia

T2 - Diabetologia

JF - Diabetologia

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ER -