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

Biomedical Sciences Research Institute Computer Science Research Institute Environmental Sciences Research Institute Nanotechnology & Advanced Materials Research Institute

Irwin, Nigel, Montgomery, IA, O'Harte, Finbarr, Frizelle, P and Flatt, Peter (2012) 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, 37 (8). pp. 1058-1063. [Journal article]

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DOI: 10.1038/ijo.2012.179

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.

Item Type:Journal article
Faculties and Schools:Faculty of Life and Health Sciences
Faculty of Life and Health Sciences > School of Biomedical Sciences
Faculty of Life and Health Sciences > School of Pharmacy and Pharmaceutical Science
Research Institutes and Groups:Biomedical Sciences Research Institute
Biomedical Sciences Research Institute > Diabetes
ID Code:24152
Deposited By:Dr Nigel Irwin
Deposited On:23 Nov 2012 11:55
Last Modified:21 Aug 2013 09:30

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