title: Evidence that the major degradation product of glucose-dependent insulinotropic polypeptide, GIP(3-42), is a GIP receptor antagonist in vivo.
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.
authors.affiliation: School of Biomedical Sciences, University of Ulster, Coleraine, N Ireland BT52 1SA, UK. va.gault@ulster.ac.uk
authors.forename: V A
authors.initials: VA
authors.lastname: Gault
authors.forename: J C
authors.initials: JC
authors.lastname: Parker
authors.forename: P
authors.initials: P
authors.lastname: Harriott
authors.forename: P R
authors.initials: PR
authors.lastname: Flatt
authors.forename: F P M
authors.initials: FP
authors.lastname: O'Harte
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D002478:Cells, Cultured; D006224:Cricetinae; D003412:Cricetulus; D005347:Fibroblasts / Q000378:metabolism; D005749:Gastric Inhibitory Polypeptide / Q000378:metabolism*; D006801:Humans; D007328:Insulin / Q000378:metabolism; D008970:Molecular Weight; D011964:Receptors, Gastrointestinal Hormone / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014162:Transfection
chemical_list: D001786:Blood Glucose; D007328:Insulin; D011964:Receptors, Gastrointestinal Hormone; D005749:Gastric Inhibitory Polypeptide; C041086:gastric inhibitory polypeptide receptor