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A novel acylated form of (d-Ala2)GIP with improved antidiabetic potential, lacking effect on body fat stores

Martin, CM, Irwin, Nigel, Flatt, Peter and Gault, Victor (2013) A novel acylated form of (d-Ala2)GIP with improved antidiabetic potential, lacking effect on body fat stores. Biochimica et Biophysica Acta, 1830 (6). pp. 3407-3413. [Journal article]

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DOI: 10.1016/j.bbagen.2013.03.011

Abstract

BACKGROUND: Rapid enzymatic degradation of the incretin hormone, glucose-dependent insulinotropic polypeptide (GIP), limits therapeutic use of the native peptide for diabetes. However, enzymatically stable analogues of GIP, such as (d-Ala2)GIP, have been generated, but are still susceptible to renal filtration.METHODS: The present study examines the in vitro and in vivo biological actions of a novel, acylated GIP analogue, (d-Ala2)GIP[Lys37PAL].RESULTS: In BRIN-BD11 cells, (d-Ala2)GIP[Lys37PAL] concentration-dependently stimulated (p<0.05 to p<0.001) insulin secretion at 5.6 and 16.7mM glucose. Intraperitoneal administration of (d-Ala2)GIP[Lys37PAL] to normal mice eight hours prior to a glucose load significantly reduced (p<0.05) the overall glycaemic excursion compared to controls, and increased (p<0.001) the insulinotropic response compared to (d-Ala2)GIP and saline treated high fat control mice. Once daily administration of (d-Ala2)GIP[Lys37PAL] for 21days in high fat fed mice did not affect energy intake, body weight or fat deposition. However, circulating blood glucose was significantly lower (p<0.05) accompanied by increased (p<0.05) insulin concentrations by day 21. In addition, (d-Ala2)GIP[Lys37PAL] treatment significantly (p<0.01) reduced the overall glycaemic excursion and increased pancreatic insulin content (p<0.05) and the insulinotropic response (p<0.01) to an exogenous glucose challenge on day 21. Chronic treatment with (d-Ala2)GIP[Lys37PAL] did not result in resistance to the metabolic effects of a bolus injection of native GIP. Finally, insulin sensitivity was significantly improved (p<0.001) in (d-Ala2)GIP[Lys37PAL] treated mice compared to high fat controls.CONCLUSIONS: These data confirm that (d-Ala2)GIP[Lys37PAL] is a stable, long-acting potent GIP agonist General significance (d-Ala2)GIP[Lys37PAL] may be suitable for further evaluation and future clinical development.

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:25403
Deposited By: Dr Nigel Irwin
Deposited On:25 Mar 2013 15:03
Last Modified:01 May 2013 13:33

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