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Degradation, insulin secretion, and antihyperglycemic actions of two palmitate-derivitized N-terminal pyroglutamyl analogues of glucose-dependent insulinotropic polypeptide

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

Irwin, Nigel, Green, BD, Gault, Victor, Greer, B, Harriott, P, Bailey, CJ, Flatt, Peter and O'Harte, Finbarr (2005) Degradation, insulin secretion, and antihyperglycemic actions of two palmitate-derivitized N-terminal pyroglutamyl analogues of glucose-dependent insulinotropic polypeptide. JOURNAL OF MEDICINAL CHEMISTRY, 48 (4). pp. 1244-1250. [Journal article]

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DOI: 10.1021/jm049262s

Abstract

Exploitation of glucose-dependent insulinotropic polypeptide (GIP) is hindered by its short biological half-life and rapid renal clearance. To circumvent these problems, two novel acylated N-terminally modified GIP analogues, N-pGluGIP(LysPAL(16)) and N-pGluGIP(LysPAL(37)), were evaluated. In contrast to native GIP, both analogues were completely resistant to dipeptidyl peptidase IV degradation. In GIP-receptor transfected fibroblasts, N-pGluGIP(LysPAL16) and N-pGluGIP(LysPAL37) exhibited enhanced stimulation of cAMP production. Insulinotropic responses in clonal beta-cells were similar to native GIP. When administered together with glucose to ob/ob mice, the glycemic excursions were significantly less for both analogues and insulin responses were greater than native GIP. Extended insulinotropic and antihyperglycemic actions were also evident. These data indicate that palmitate-derivitized analogues of N-terminal pyroglutamyl GIP represent a novel class of stable, long-acting, and effective GIP analogues for potential type 2 diabetes therapy.

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:3006
Deposited By:Professor Peter Flatt
Deposited On:18 Dec 2009 10:07
Last Modified:19 Nov 2012 16:22

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