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Evidence that the major degradation product of glucose-dependent insulinotropic polypeptide, GIP(3-42), is a GIP receptor antagonist in vivo

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Gault, Victor, Parker, JC, Harriott, P, Flatt, Peter and O'Harte, Finbarr (2002) Evidence that the major degradation product of glucose-dependent insulinotropic polypeptide, GIP(3-42), is a GIP receptor antagonist in vivo. JOURNAL OF ENDOCRINOLOGY, 175 (2). pp. 525-533. [Journal article]

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Abstract

The incretin hormone glucose-dependent insulinotropic polypeptide (GIP) is rapidly degraded in the circulation by dipeptidyl peptidase IV forming the N-terminally truncated peptide GIP(3-42). The present study examined the biological activity of this abundant circulating fragment peptide to establish its possible role in GIP action. Human GIP and GIP(3-42) were synthesised by Fmoc solid-phase peptide synthesis, purified by HPLC and characterised by electrospray ionisation-mass spectrometry. In GIP receptor-transfected Chinese hamster lung fibroblasts, GIP(3-42) dose dependently inhibited GIP-stimulated (10(-7) M) cAMP production (up to 75.4 +/-5.4%; P<0.001). In BRIN-BD11 cells, GIP(3-42) was significantly less potent at stimulating insulin secretion (1.9- to 3.2-fold; P<0.001), compared with native GIP and significantly inhibited GIP-stimulated (10 7 M) insulin secretion with maximal inhibition (48.8 +/- 6.2%; P<0.001) observed at 10(-7) M. In (ob/ob) mice, administration of GIP(3-42) significantly inhibited GIP-stimulated insulin release (2.1-fold decrease; P<0.001) and exaggerated the glycaemic excursion (1.4-fold; P<0.001) induced by a conjoint glucose load. These data indicate that the N-terminally truncated GIP(3-42) fragment acts as a GIP receptor antagonist, moderating the insulin secreting and metabolic actions of GIP in vivo.

Item Type:Journal article
Faculties and Schools:Faculty of Life and Health Sciences
Faculty of Life and Health Sciences > School of Biomedical Sciences
Research Institutes and Groups:Biomedical Sciences Research Institute
Biomedical Sciences Research Institute > Diabetes
ID Code:3058
Deposited By:Professor Peter Flatt
Deposited On:13 Jan 2010 16:20
Last Modified:11 Jun 2010 11:56

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