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Animal Models

Comparison of the independent and combined metabolic effects of subchronic modulation of CCK and GIP receptor action in obesity-related diabetes

International Journal of Obesity volume 37, pages 1058–1063 (2013)Cite this article

Subjects

Abstract

OBJECTIVE:

Compromise of gastric inhibitory polypeptide (GIP) receptor action and activation of cholecystokinin (CCK) receptors represent mechanistically different approaches to the possible treatment of obesity-related diabetes. In the present study, we have compared the individual and combined effects of (Pro3)GIP[mPEG] and (pGlu-Gln)-CCK-8 as an enzymatically stable GIP receptor antagonist and CCK receptor agonist molecule, respectively.

RESULTS:

Twice-daily injections of (pGlu-Gln)-CCK-8 alone and in combination with (Pro3)GIP[mPEG] in high-fat-fed mice for 34 days significantly decreased the energy intake throughout the entire study (P<0.05 to P<0.01). Body weights were significantly depressed (P<0.05 to P<0.01) in all treatment groups from day 18 onwards. Administration of (pGlu-Gln)-CCK-8, (Pro3)GIP[mPEG] or a combination of both peptides significantly (P<0.01 to P<0.001) decreased the overall glycaemic excursion in response to both oral and intraperitoneal glucose challenge when compared with the controls. Furthermore, oral glucose tolerance returned to lean control levels in all treatment groups. The beneficial effects on glucose homeostasis were not associated with altered insulin levels in any of the treatment groups. In keeping with this, the estimated insulin sensitivity was restored to control levels by twice-daily treatment with (pGlu-Gln)-CCK-8, (Pro3)GIP[mPEG] or a combination of both peptides. The blood lipid profile on day 34 was not significantly different between the high-fat controls and all treated mice.

CONCLUSION:

These studies highlight the potential of (pGlu-Gln)-CCK-8 and (Pro3)GIP[mPEG] in the treatment of obesity-related diabetes, but there was no evidence of a synergistic effect of the combined treatment.

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Acknowledgements

These studies were supported by the SAAD Trading and Contracting Company and the Department of Education and Learning, Northern Ireland.

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Authors and Affiliations

  1. SAAD Centre for Pharmacy and Diabetes, School of Biomedical Sciences, University of Ulster, Coleraine, Northern Ireland, UK

    N Irwin, I A Montgomery, F P M O'Harte, P Frizelle & P R Flatt

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  1. N Irwin
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  2. I A Montgomery
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  4. P Frizelle
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Correspondence to N Irwin.

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Competing interests

NI, FPMO’H and PRF hold shares in Diabetica Ltd, which has patents for the exploitation of peptide therapeutics.

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Irwin, N., Montgomery, I., O'Harte, F. et al. Comparison of the independent and combined metabolic effects of subchronic modulation of CCK and GIP receptor action in obesity-related diabetes. Int J Obes 37, 1058–1063 (2013). https://doi.org/10.1038/ijo.2012.179

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