Characterization and biological actions of N-terminal truncated forms of glucose-dependent insulinotropic polypeptide

• Published in: Biochemical and biophysical research communications Vol. 404; no. 3; pp. 870 - 876
• Main Authors: Kerr, Barry D., Flatt, Anneliese J.S., Flatt, Peter R., Gault, Victor A.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 21.01.2011
• Subjects: amino acid substitution; animal disease models; Animals; antagonists; bioactive properties; blood glucose; cyclic AMP; Cyclic AMP - biosynthesis; Gastric Inhibitory Polypeptide - chemistry; Gastric Inhibitory Polypeptide - pharmacology; gastric inhibitory polypeptide receptors; gastrointestinal hormones; GIP antagonist; Glucose - metabolism; Glucose lowering; Glucose-dependent insulinotropic polypeptide (GIP); insulin; Insulin - metabolism; Insulin Secretion; Mice; Mice, Inbred Strains; noninsulin-dependent diabetes mellitus; ob/ ob mice; polypeptides; Protein Structure, Tertiary; Receptors, Gastrointestinal Hormone - antagonists & inhibitors; structure-activity relationships; Glucose lowering; Glucose-dependent insulinotropic polypeptide (GIP); GIP antagonist; ob/ ob mice; Insulin secretion
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2010.12.077

► Bioactivity of 9 N-terminal truncated GIP peptides were examined in vitro and in vivo. ► GIP(4-42), GIP(5-42), GIP(7-42) and GIP(8-42) inhibited GIP-induced cAMP production. ► GIP(4-42), GIP(5-42), GIP(7-42) and GIP(8-42) decreased GIP-induced insulin secretion. ► GIP(8-42) significantly countered hyperglycaemic and insulin-releasing actions of GIP. ► Sequential truncation of GIP yields antagonists with functional significance. 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.