title: Characterization and biological actions of N-terminal truncated forms of glucose-dependent insulinotropic polypeptide.
abstract: The N-terminal domain of glucose-dependent insulinotropic polypeptide (GIP) plays an important role in regulating biological activity. This study examined biological properties of several N-terminal truncated forms of GIP and two novel forms with substitutions at Phe position-6 with Arg or Val. GIP(6-42), GIP(R6-42), GIP(V6-42), GIP(7-42) and GIP(9-42) stimulated cAMP production in BRIN-BD11 cells similar to native GIP, whereas responses to GIP(3-42), GIP(4-42), GIP(5-42) and GIP(8-42) were reduced (P<0.01 to P<0.001). GIP-induced cyclic AMP production was significantly inhibited by GIP(3-42), GIP(4-42), GIP(5-42), GIP(6-42), GIP(R6-42), GIP(7-42) and GIP(8-42) (P<0.001). Compared with native GIP, in vitro insulinotropic activity of GIP(3-42), GIP(4-42), GIP(5-42), GIP(7-42) and GIP(8-42) was reduced (P<0.05 to P<0.001), with GIP(4-42), GIP(5-42), GIP(7-42) and GIP(8-42) also potently inhibiting GIP-stimulated insulin secretion (P<0.001). In ob/ob mice, GIP(4-42) and GIP(8-42) increased (P<0.05 to P<0.01) plasma glucose concentrations compared to the glucose-lowering action of native GIP. When GIP(8-42) was co-administered with native GIP it countered the ability of the native peptide to lower plasma glucose and increase circulating insulin concentrations. These data confirm the importance of the N-terminal region of GIP in regulating bioactivity and reveal that sequential truncation of the peptide yields novel GIP receptor antagonists which may have functional significance.
authors.affiliation: School of Biomedical Sciences, University of Ulster, Coleraine, Northern Ireland, UK.
authors.forename: Barry D
authors.initials: BD
authors.lastname: Kerr
authors.forename: Anneliese J S
authors.initials: AJ
authors.lastname: Flatt
authors.forename: Peter R
authors.initials: PR
authors.lastname: Flatt
authors.forename: Victor A
authors.initials: VA
authors.lastname: Gault
mesh_terms: D000818:Animals; D000242:Cyclic AMP / Q000096:biosynthesis; D005749:Gastric Inhibitory Polypeptide / Q000737:chemistry* / Q000494:pharmacology*; D005947:Glucose / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D051379:Mice; D008815:Mice, Inbred Strains; D017434:Protein Structure, Tertiary; D011964:Receptors, Gastrointestinal Hormone / Q000037:antagonists & inhibitors*
chemical_list: D007328:Insulin; D011964:Receptors, Gastrointestinal Hormone; D005749:Gastric Inhibitory Polypeptide; C041086:gastric inhibitory polypeptide receptor; D000242:Cyclic AMP; D005947:Glucose