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(pGlu-Gln)-CCK-8[mPEG]: A novel, long-acting, mini-PEGylated cholecystokinin (CCK) agonist that improves metabolic status in dietary-induced diabetes

Irwin, Nigel, Frizelle, P, O'Harte, Finbarr and Flatt, Peter (2013) (pGlu-Gln)-CCK-8[mPEG]: A novel, long-acting, mini-PEGylated cholecystokinin (CCK) agonist that improves metabolic status in dietary-induced diabetes. Biochimica et Biophysica Acta - General Subjects, 1830 (8). pp. 4009-4016. [Journal article]

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DOI: 10.1016/j.bbagen.2013.04.004

Abstract

BACKGROUND: Cholecystokinin (CCK) is a gastrointestinal hormone that has been proposed as a potential therapeutic option for obesity-diabetes. As such, (pGlu-Gln)-CCK-8 is an N-terminally modified CCK-8 analogue with improved biological effectiveness over the native peptide.METHODS: The current study has examined the in vitro stability, biological activity and in vivo therapeutic applicability of a novel second generation mini-PEGylated form of (pGlu-Gln)-CCK-8, (pGlu-Gln)-CCK-8[mPEG].RESULTS: (pGlu-Gln)-CCK-8[mPEG] was completely resistant to enzymatic degradation and in addition displayed similar insulinotropic (p<0.05 to p<0.001) and satiating effects (p<0.01 to p<0.001) as (pGlu-Gln)-CCK-8. This confirmed the capability of (pGlu-Gln)-CCK-8[mPEG] to bind to and activate the CCK receptor. Sub-chronic twice daily injection of (pGlu-Gln)-CCK-8[mPEG] in high fat fed mice for 35days significantly decreased body weight gain (p<0.05), food intake (p<0.01 to p<0.001) and triacylglycerol deposition in liver (p<0.001) and muscle (p<0.001). Furthermore, (pGlu-Gln)-CCK-8[mPEG] markedly improved intraperitoneal glucose tolerance (p<0.05) and insulin sensitivity (p<0.001). Despite this therapeutic profile, once daily injection of (pGlu-Gln)-CCK-8[mPEG] in high fat fed mice for 33days, at the same dose, was not associated with alterations in food intake and body weight. In addition, metabolic responses to exogenous glucose and insulin injection were similar to saline treated controls.CONCLUSION: These studies emphasise the therapeutic potential of (pGlu-Gln)-CCK-8[mPEG] and similar molecules GENERAL SIGNIFICANCE: A more detailed analysis of the dose and administration schedule employed for (pGlu-Gln)-CCK-8[mPEG] could provide a novel and effective compound to treat obesity-diabetes.

Item Type:Journal article
Faculties and Schools:Faculty of Life and Health Sciences > School of Biomedical Sciences
Faculty of Life and Health Sciences > School of Pharmacy and Pharmaceutical Science
Faculty of Life and Health Sciences
Research Institutes and Groups:Biomedical Sciences Research Institute
Biomedical Sciences Research Institute > Diabetes
ID Code:25790
Deposited By: Dr Nigel Irwin
Deposited On:23 Apr 2013 08:45
Last Modified:10 Jun 2013 09:28

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