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Antagonism of gastric inhibitory polypeptide (GIP) by palmitoylation of GIP analogues with N- and C-terminal modifications improves obesity and metabolic control in high fat fed mice

Pathak, V, Gault, Victor, Flatt, Peter and Irwin, Nigel (2015) Antagonism of gastric inhibitory polypeptide (GIP) by palmitoylation of GIP analogues with N- and C-terminal modifications improves obesity and metabolic control in high fat fed mice. Molecular and Cellular Endocrinology, 401 . pp. 120-129. [Journal article]

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DOI: 10.1016/j.mce.2014.10.025

Abstract

Compromise of gastric inhibitory polypeptide (GIP) receptor signalling represents a possible therapeutic strategy for the treatment of obesity-related diabetes. This study has characterised and evaluated the C-terminally fatty acid derivatised GIP analogues, GIP(3-30)Cex-K40[Pal] and Pro3GIP(3-30)Cex-K40[Pal], as potential GIP inhibitors. Both GIP analogues lack the two N-terminal amino acids cleaved by DPP-4 and have addition of nine amino acids from the C-terminal of exendin(1-39), Cex. GIP(3-30)Cex-K40[Pal] and Pro3GIP(3-30)Cex-K40[Pal] effectively (p < 0.01 to p < 0.001) inhibited GIP-induced cAMP production and insulin secretion in vitro. In normal mice, GIP(3-30)Cex-K40[Pal] and Pro3GIP(3-30)Cex-K40[Pal] displayed a significant (p < 0.05 to p < 0.001) and prolonged inhibitory effect on GIP-induced glucose-lowering and insulin-releasing actions. When injected once daily for 21 days in obese-diabetic high fat fed mice, both GIP(3-30)Cex-K40[Pal] and Pro3GIP(3-30)Cex-K40[Pal] significantly reduced body weight (p < 0.01 to p < 0.001) and lowered circulating glucose (p < 0.001) and insulin (p < 0.01 to p < 0.001) concentrations. The observed beneficial changes were independent of effects on energy intake, locomotor activity or metabolic rate. Oral and intraperitoneal glucose tolerance were significantly (p < 0.05 to p < 0.001) improved in both treatment groups at the end of the study, despite reduced glucose-induced plasma insulin concentrations. This improvement of metabolic control was accompanied by enhanced (p < 0.05 to p < 0.01) insulin sensitivity compared with high fat controls. These data demonstrate the potential offered by GIP(3-30)Cex-K40[Pal] and Pro3GIP(3-30)Cex-K40[Pal] for the treatment of obesity-related diabetes.

Item Type:Journal article
Faculties and Schools:Faculty of Life and Health Sciences > School of Pharmacy and Pharmaceutical Science
Faculty of Life and Health Sciences > School of Biomedical Sciences
Faculty of Life and Health Sciences
Research Institutes and Groups:Biomedical Sciences Research Institute
Biomedical Sciences Research Institute > Diabetes
ID Code:30768
Deposited By: Dr Nigel Irwin
Deposited On:08 Jan 2015 09:26
Last Modified:09 May 2016 11:21

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