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

N‐terminally and C‐terminally truncated forms of glucose‐dependent insulinotropic polypeptide are high‐affinity competitive antagonists of the human GIP receptor

“…Only GIP(8–42), with a E max of 10% in terms of cAMP release, was able to antagonize the action of GIP(1–42) in vivo with decreased insulin secretion and increased plasma glucose in an acute setting. In line with our results with GIP(5–30)NH 2 , GIP(5–42) was the most potent antagonist in vitro ; however, the length‐dependent functional changes described here for the human GIP(1–30)NH 2 variants were not observed in the truncated GIP(1–42) variants (Kerr et al , ). All together, this indicates that the C‐terminus is important for intrinsic activity, and even though the activities of GIP(1–30)NH 2 and GIP(1–42) are similar, the N‐terminally truncated GIP variants reveal that the C‐terminus (position 31–42) improves intrinsic activity.…”

“…C-terminus had a huge negative impact, as GIP(3-30)NH 2 was a 26-fold more potent antagonist compared with GIP(3-42). Taken together, our study combined with previous studies Wheeler et al, 1995;Morrow et al, 1996;Tseng et al, 1996;Hinke et al, 2001;Kerr et al, 2011) indicates that the C-terminus (position 31-42) has only a minute impact on the binding and no impact on the agonistic properties of GIP (with preserved N-terminus), whereas it affects the functionality of the N-terminally truncated GIP variants. Thus, the presence of the C-terminus enhances the intrinsic activity (confers agonism) to GIP(3-to 8-42) (Kerr et al, 2011), while the absence of it in our GIP(3-to 9-30)NH 2 variants improves the antagonism.…”

“…In a previous study, consecutive N‐terminal truncations of human GIP(1–42) were characterized in vitro in the rat GIP receptor and in leptin mutant mice (Kerr et al , ). In contrast to our findings for the similar truncations in the human GIP(1–30)NH 2 scaffold, GIP(3‐ to 8–42) displayed partial agonism, and GIP(9–42) acted as a full GIP receptor agonist in vitro .…”

What doesn't kill you makes you stranger: Dipeptidyl peptidase-4 (CD26) proteolysis differentially modulates the activity of many peptide hormones and cytokines generating novel cryptic bioactive ligands

“…In contrast GIP(3-42) leads to an initial increase in glucose reaching its peak after 15 minutes, before it starts to decrease. Administration of other N-terminal cleaved GIP isoforms to ob/ob mice, like GIP(8-42), also showed a significant inhibition to intact GIP glucose lowering effect (Kerr, et al, 2011).…”

Species‐specific action of (Pro3)GIP – a full agonist at human GIP receptors, but a partial agonist and competitive antagonist at rat and mouse GIP receptors

“…Inspired by this, researchers have tried to develop a potent GIP receptor antagonist. Many different strategies have been undertaken in order to inhibit GIP function, including prepro ‐GIP gene truncations (Nasteska et al ., ), administration of low MW receptor antagonists (Nakamura et al ., ), immunization against GIP (Ebert et al ., ; Fulurija et al ., ; Irwin et al ., ), various truncations and amino acid substitutions of the GIP molecule thought to provide antagonistic properties (Tseng et al ., ; Gelling et al ., ; Hinke et al ., ; Gault et al ., ; Deacon et al ., ; Irwin et al ., ; Kerr et al ., ), and recently, a potent antagonistic antibody against the GIP receptor was reported (Ravn et al ., ). However, most attention has been given to the analogue (Pro3)GIP following demonstrations that chronic treatment with this peptide improved diabetic parameters in ob / ob mice (Irwin et al ., ), improved diabetic parameters and induced weight loss in obese mice previously on a high‐fat diet (McClean, ), and reduced weight gain and improved diabetic parameters following the induction of a high‐fat diet (Gault et al ., ).…”